Lupine Publishers | Route evaluation of domestic violence and epileptic seizure (“fit”) experience among recently married women residing inslums communities’pharmaceutical institutions in Pune District, India

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

An attack of an acute disease or the sudden appearance of over symptom, such as coughing and convulsion accepted as ‘’Fit’’. In 2015, epilepsy affected 1.2 percent of the population in the United States, or 3.4 million people, including 3 million adults and 470,000 children. Every function in the human body has triggered by messaging systems in our brain. Epilepsy results when this system has disrupted due to faulty domestic violations. The Centers for Disease Control and Prevention (CDC) describe epilepsy as “a common neurological condition that kept under control and medically care. It has mainly control slowing advance, rather, it must submit their claims to rigorous non-scientific culture.

Opinion

In many cases, the exact cause has not known. Some people have inherited genetic factors that make epilepsy more likely to occur. Other factors that may increase the risk include: head trauma, for instance, during a car crash, stroke infectious diseases, for instance, AIDS and viral encephalitis, developmental disorders, for instance, autism or neurofibromatosis. It has most likely to appear in children under 2 years of age very rare, middle age and adults over 65 years. What a patient with epilepsy experiences during a seizure will depend on which part of the brain has affected, and how widely and quickly it spreads from that area. The incomplete note of medical sciences that the condition “has not well understood.” Often, no specific cause can be identified. Intimate partner violence (IPV), defined as the physical, sexual, psychological abuse, and control perpetrated against an intimate partner, has highly prevalent and cannot ignore for epilepsy epidemic. Approximately one in ten of women reporting physical and abuse by their partner during their lifetime, violation of human rights that often results in physical injury can lead neurological disturbances (trauma). Women who experience IPV have higher odds of depression, anxiety and other mental health disorders, [1] sexually transmitted infections including HIV, [2] chronic pain disorders and gynaecologic morbidity among other chronic disease states lead the epileptic seizure (“fit”). Additionally, their children suffer from greater symptom of epilepsy morbidity and mortality.

In India, although national estimates suggest decreasing frequency, one in three women still report having been abused by their spouses during their lifetime. Further, this figure has likely an underestimate of the abuse women suffer post-epileptic seizer or other members of the husband’s family, hereafter termed domestic violence (DV). Women who reside in India’s slums pharmaceutical institutions are among those at greatest risk of high fever with epilepsy-like symptoms. While the disparate figures between slum- and non-slum residing communities may be in part art efactual due to shame induced underreporting in higher income communities, factors that drive increased DV perpetration and compel women to remain in abusive relationships are likely disproportionately greater in slum to slum communities. Women in slum communities may be more likely to experience DV with periods of extreme muscle weakness because their partners and families into which they marry suffer greater stress (i.e. related to inadequate finances, crowding, limited resources, low update oxygen and poor sanitation), discrimination, and subordination, reside in communities where normalization and acceptance of DV has greater, alcohol use has greater, have weakened immune support systems that do not allow them to develop and exercise positive coping mechanisms, and epileptic disorder use as means of countering feelings of powerlessness.

Further, in Pune district slum communities, at the time of marriage, many women transition from newly enter the slums from surrounding rural areas; thus, the differences in upbringing within the couple may also influence marital expectations and prompt conflict. Further, women residing in slums may be more likely to stay in panic attacks because of poorer knowledge of and access to health support services, on time medicine and increased economic dependence, [3] weaker support systems, stronger perceptions of hopelessness, and residence in environments where DV and other forms of psychogenic seizures occurs with frequency and acceptance willingly [4]. The risk imposed by these factors has compounded by social sanctions that encourage women to weaken ties with (and thus, diminish the social support of) natal family members and their community post-marriage, that limit the time the couple spends together alone to develop their relationship both pre-and post-marriage, and external pressure on the couple (i.e. fertility). Further, women’s financial empowerment through employment, a seemingly logical solution, has counter intuitively been shown to be associated with increased DV experience through challenging traditional gender roles and serving as a threat to male partners. Thus, there are currently cure for most types of correlate Domestic Violation epilepsy. However, surgery can stop some kinds of seizure from occurring, and in many cases, the condition can be managed. An underlying correctable brain condition has causing the seizures, sometimes surgery can stop them. Epilepsy has diagnosed; the doctor will prescribe seizure-preventing drugs or anti-epileptic drugs.

The majority of AEDs are taken orally. The type of seizure the patient has having will decide which drug the doctor may prescribe. Patients do not all react in the same way to drugs, but AEDs appear to help control seizures in 70 percent of cases. Some drugs may stop seizures in one patient, but not in another. Even when the right drug has found, it can take some time to find the ideal dose. Drugs do not work; the next option could be surgery, a special diet or VNS (vagus nerve stimulation).The doctor’s aim has to prevent further seizures from occurring, while at the same time avoiding side effects so that the patient can lead a normal, active, and productive life. A community-tailored approach that recognizes the structural factors of slum environments that shape DV risk reduce. National evidence suggests that almost two-thirds of women who report DV with Fit, state the abuse had begun within the first two years of marriage, [5] underscoring the need for such prevention efforts to occur preor immediately post-marriage. To date, few studies have examined risk factors for DV experience among women residing in slum communities in India. Those who have, identified the following risk factors: age, low educational attainment of self and spouse, young age of marriage, having a love marriage versus arranged marriage, additional dowry request from marital family, employment, changes in her own or her spouse’s employment status, residence in a joint family, renting versus owning one’s residence, fewer rooms in the household and shared bathrooms, accepting attitudes toward wife beating.

Discussion

Epilepsy has neurological condition that can kept under control. Drugs commonly used to treat epilepsy include: sodium valproate and carbamazepine. Consultation authenticated hospitals or government hospitals, indoor treatment at government and empanelled private hospitals and investigations at government and empanelled diagnostic centers.

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Lupine Publishers | Preparation of Morphine Derivatives Using Ionic Liquids

Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

Dextromethorphan, an anti tussive drug belongs to the morphinan family, and is mostly available in the market as a combination therapy. Most of the reported preparation procedures involve the use of racemic starting materials that give lower yields. (S)- Octa base is one of the key starting raw materials used in our process and this easy, convenient and eco-friendly preparation (single step) is reported in this manuscript. This drug, Dextromethorphan is produced in large volumes annually (> 150 tons/year). Most reported synthetic procedures make use of huge amounts of volatile organic solvents which are hazardous for environment. This will be a major issue in the near future. To overcome this problem, we have tried using Ionic liquid as a solvent in the preparation and successfully arrived at best results, thereby decreasing the use of organic volatile solvents.

Keywords: Dextromethorphan, Morphine derivatives, Alkaloids, Formylation, Ionic liquid

Introduction

Dextromethorphan, a drug of the morphinan family, is having tranquilizing, dissociative, and restorative properties (especially at higher doses). It is a cough suppressant (ANTI-TUSSIVE) in several over-the-counter cold and cough medicines including generic labels and store brands, Benylin, Mucinex, Camydex 20 tablets, Robitussin, NyQuil, Vicks, Delsym, TheraFlu, Cheracol D, and others. It has also found plentiful other uses in medication, extending from analgesic effect to psychological submissions useful in the treatment of addiction. It is sold in syrup, capsule, and lozenge forms. In its unadulterated form, Dextromethorphan ensues as a white powder. Currently, Dextromethorphan is not registered in the Schedules of the United Nations 1961 Convention on Narcotic Drug [1].

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It’s IUPAC name is (+)-3-methoxy-17-methyl-9α, 13α, 14α-morphinan. It occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydro bromide salt is water-soluble up to 1.5g/100mL at 25 °C. It is usually accessible as the monohydrated hydro bromide salt. However, some newer extended-release formulations contain Dextromethorphan bound to an ion-exchange resin based on polystyrene sulfonic acid (Picture 1).

Picture 1: Chemical structure of Dextromethorphan Hydro bromide.

Mechanism of Action

Dextromethorphan is a synthetic compound and acts as a dissociative anesthetic when taken in higher doses. Its mechanism of action is via multiple effects, plus actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist [2]. Dextromethorphan and its major metabolite, Dextrorphan, also act as NMDA receptor antagonist at high doses, which produces effects similar to other dissociative anesthetics such as ketamine and phencyclidine [3]. The metabolic pathway continues from dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan (Figure 1) [4].

Figure 1: Explains the metabolic pathway of the drug Dextromethorphan.

In one of the reported processes for the preparation of morphinan alkaloids, racemic hydroxy N- methyl morphinan is used as a starting material, an optically inactive isomer and is treated with tartaric acid for resolution to obtain selective one isomer (+) of morphinan. (PATENT- US2676177 (Roche, 1954, CHprior. 1949)) (Scheme 1).

Scheme 1: This scheme explains the reported procedure that uses a racemic hydroxy N- methyl morphinan as a starting material along with the use of solvents.

In a similar procedure reported in PATENT- CN102977021 A, Method for preparation of Dextromethorphan hydro bromide By Cui, Dapeng et al From Faming Zhuanli Shenqing, 102977021, 20 Mar 2013, Raney Nickel as a reducing agent is replaced by KBH4, thus, reducing the cost. Also, resolution is done with R-ibuprofen for the first time. Another advantage is the use of AlCl3 is adopted to replace H3PO4 to cyclize. Overall, it is a low cost, moderate reaction conditions, easy in operation and suitable for industrial production (Scheme 2).

Further, in the search for better preparation methods, which is easier, lesser preparation steps, cost effective, and also using chemicals that are easy to handle and can provide higher yields as well as purity, it has been found that the critical step of Grewe’s cyclization is reported in a paper titled, ‘A Novel synthesis of substituted 1-benzyloctahydroisoquinolines by acid-catalyzed cyclization of N-[2-(Cyclohex-1-enyl]-N-styryl formamides’ [5] (Scheme 3).

Scheme 2: Explains another reported procedure, where alternate reagents like KBH4, R-ibuprofen and AlCl3 have been used to refine the existing method of preparation of Dextromethorphan.

Scheme 3: Explains a reported procedure involving the preparation of Dextromethorphan that involves Grewe`s cyclization.

Scheme 4: Explains a reported procedure of Dextromethorphan preparation, where formylation was done before the cyclization step to improve the yield.

According to this paper, no cyclization of enamide was observed with Lewis acid catalyst (AlCl3, AlEtCl2, TiCl4), Two equivalents of BF3-Et2O was used, and complete conversion was observed. In all cyclization reactions, a side product is formed that is more polar than the octa hydroisoquinolines and N-formyl octa hydroisoquinolines synthesized from N-formyl- 2-phenylethylamines and benzaldehyde. Also, reduction of N-formaldehyde to N-methylated was done using LiAlH4. While going through literature, it was found that formylation before cyclisation avoids ether cleavage as a side reaction and higher yields were obtained than without N-substitution or N-methylation. In this patent, purification/resolution was done using the formation of Brucine salt (US3634429 (Jan 11, 1972) Morphinan derivatives and preparation there of (Scheme 4).

Experimental and Results

All the above-mentioned processes involve the use of solvents. So, in the existent investigation, an endeavor is explored to develop an alternate process wherein use of solvents can be avoided in the synthesis of Dextromethorphan (Scheme 5).

Scheme 5: Explains a greener preparation of Dextromethorphan using an Ionic Liquid.

Preparation of Dextromethorphan Hydrobromide using 1-butyl-3-methyl imidazolium acetate (Ionic liquid) as a solvent

I-step:

a) Stage-IA: In a flask, charge 1-butyl-3-methyl imidazolium acetate under nitrogen atmosphere. Charge (S)-Octa base under nitrogen atmosphere. Cool if required under nitrogen atmosphere. Charge Sodium methoxide solution in methanol under nitrogen atmosphere. Charge Methyl formate. Raise the temperature of the reaction mass to little reflux by using hot water not more than 55oC. Stir and maintain the reaction mass till reaction complies (2 hours). Concentrate the reaction mass u/v (Capacity of vacuum pump should be > 700 mm/Hg) till almost no solvent distills. To the concentrated reaction mass, charge toluene under nitrogen atmosphere and water extraction is done. The extracted toluene layer was concentrated to give N-Formyl octa base and is used as such.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 1) and (Picture 2).

Table 1: s- singlet, m-multiplet, br-broad.

Picture 2:

b) Stage-IB: In another flask, charge Ortho phosphoric acid (~ 85.0 % w/w). Charge Toluene and Raise the temperature of the reaction mass. Reflux and maintain over Dean stark apparatus to remove water azeotropically. Cool the reaction mass under nitrogen atmosphere and Charge Phosphorus pentoxide under nitrogen atmosphere. Reaction is highly exothermic. Charge 1-butyl-3-methyl imidazolium acetate. Slowly add N-formyl octa base and Raise the temperature of the reaction mass under nitrogen atmosphere. Stir and maintain the reaction mass at 65-70oC under nitrogen atmosphere till reaction complies. Concentrate the reaction mass under vacuum to remove toluene. To the concentrated mass, charge ethyl acetate under nitrogen atmosphere and stir. In another flask, charge water, Cool. Charge ethyl acetate reaction mixture reaction mass in to chilled water. Stir, settle and separate the layers. Repeat for back extraction. Wash the organic layer with water again and then a wash of 7% sodium bicarbonate solution is given. Concentrate the organic layer u/v till almost no solvent distills. Degas the concentrate u/v to remove traces of solvents.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 2) and (Picture 3)

Table 2: s- singlet, m-multiplet, br-broad.

Picture 3:

c) Stage-IC: To the concentrate mass, charge 1-butyl- 3-methyl imidazolium acetate and methanol under nitrogen atmosphere. Stir and slowly add sodium hydroxide solution Pre- Cooled ~15oC (Prepare by using 109 g Sodium hydroxide dissolved in 200ml Water). Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~15 hours). Concentrate the reaction mass u/v. To the concentrate mass, charge toluene under nitrogen atmosphere and water workup is done. The extracted toluene layer was concentrated to give N-Nordextromethorphan (Stage-IC).

m/z (M+H+) - 258

NMR chemical shift values tabulated below (Table 3) and (Picture 4):

Table 3: s- Singlet, m-multiplet, br-broad.

Picture 4:

d) Stage-ID: To the mixture of1-butyl-3-methyl imidazolium acetate and N-Nordextromethorphan (Stage-IC), slowly add Formic acid solution (Prepare by using 32.1g Formic acid diluted with 5.7ml water). Charge Formaldehyde solution. Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~2 hours). After the reaction is complete, Charge water and cool the reaction mass if required and then slowly add sodium hydroxide solution Pre-cool (< 15 oC) (Prepared by using 28.0g Sodium hydroxide dissolved in 140ml water), extracted the product into toluene, again charge water, cool, and slowly add Hydrobromic acid. Raise the temperature of the reaction mass to 70-80 oC and Stir and maintain to get clear solution. The organic and aqueous layers separated. Cool the Aqueous layer under stirring to get precipitate and further cooled to 3-6 oC and wash with pre-chilled water. Dry the solid under vacuum, to get Dextromethorphan hydro bromide.

m/z (M+H+) - 272

NMR chemical shift values tabulated below (Table 4) and (Picture 5):

Table 4: s- Singlet, d- doublet, m-multiplet, br-broad.

Picture 5:

a) 1H-1H coupling constants.

Discussion

As of today, chemical manufacturing process of APIs in pharmaceutical industry is handicapped without the use of chemical solvents. However, it is a scientifically known fact that solvents are dangerously damaging chemical entities, mainly of the following reasons:

a) Volatile nature of solvents.

b) Storage and handling risks.

c) Usage requirements in large scale.

Apart from their handling risks to human beings, they also cause significant saturation in chemical pollution levels in the environment; there has been constant research going-on in academic field as well as industries to find their suitable alternative [6].

Ionic liquids are one such alternative that has been found useful to substitute the commonly used bench solvents. Other than their obvious “solvent” property that have been discussed in various publications [7-10], they have also been found to catalyze certain type of reactions in which they participate [11-13]. Moreover, their complete recovery from the reaction is an easy job when juxtaposed with their volatile solvent counterparts. For this reason, an ionic liquid can be re-cycled for multiple batches of reactions.

Another unique property of ionic liquids is that they can be “tailor-made” to suit specific reaction types by playing around with the cation and anion part of them. They are called as “task-specific ionic liquids”. These tailored [14] and specially synthesized ionic liquids have more scope of their application in a chemical reaction than just acting as a green solvent.

Conclusion

A simple, efficient, eco-friendly synthetic route is developed involving the single-step synthesis of Dextromethorphan Hydrobromide that is high on convenience and also a cost-effective procedure. This process is best suitable for the preparation of Dextromethorphan Hydrobromide and is scalable in plant. This synthetic route using an ionic liquid adapts a cleaner chemistry that assures both risk-free handling and reduced environmental pollution, when scaled-up.

Acknowledgement

Our group would like to thank the Department of Scientific and Industrial Research India, Dr. Hari Babu (COO Mylan), Sanjeev Sethi (Chief Scientific Officer Mylan Inc ); Dr Abhijit Deshmukh (Head of Global OSD Scientific Affairs); Dr Yasir Rawjee {Head-Global API (Active Pharmaceutical Ingredients)}, Dr Sureshbabu Jayachandra (Head of Chemical Research) Mr Manoj Pananchukunnath (Head of Global Injectables Scientific Affairs, Product Development) Dr. Suryanarayana Mulukutla (Head Analytical Dept MLL API R & D) as well as analytical development team of Mylan Laboratories Limited for their encouragement and support. We would also like to thank Dr Narahari Ambati (AGC- India IP) & his Intellectual property team for their support.

Read More About Lupine Publishers Journal of Chemical Sciences Please Click on Below Link:
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Lupine Publishers | Preparation of Morphine Derivatives Using Ionic Liquids

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

Dextromethorphan, an anti tussive drug belongs to the morphinan family, and is mostly available in the market as a combination therapy. Most of the reported preparation procedures involve the use of racemic starting materials that give lower yields. (S)- Octa base is one of the key starting raw materials used in our process and this easy, convenient and eco-friendly preparation (single step) is reported in this manuscript. This drug, Dextromethorphan is produced in large volumes annually (> 150 tons/year). Most reported synthetic procedures make use of huge amounts of volatile organic solvents which are hazardous for environment. This will be a major issue in the near future. To overcome this problem, we have tried using Ionic liquid as a solvent in the preparation and successfully arrived at best results, thereby decreasing the use of organic volatile solvents.

Keywords: Dextromethorphan, Morphine derivatives, Alkaloids, Formylation, Ionic liquid

Introduction

Dextromethorphan, a drug of the morphinan family, is having tranquilizing, dissociative, and restorative properties (especially at higher doses). It is a cough suppressant (ANTI-TUSSIVE) in several over-the-counter cold and cough medicines including generic labels and store brands, Benylin, Mucinex, Camydex 20 tablets, Robitussin, NyQuil, Vicks, Delsym, TheraFlu, Cheracol D, and others. It has also found plentiful other uses in medication, extending from analgesic effect to psychological submissions useful in the treatment of addiction. It is sold in syrup, capsule, and lozenge forms. In its unadulterated form, Dextromethorphan ensues as a white powder. Currently, Dextromethorphan is not registered in the Schedules of the United Nations 1961 Convention on Narcotic Drug [1].

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It’s IUPAC name is (+)-3-methoxy-17-methyl-9α, 13α, 14α-morphinan. It occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydro bromide salt is water-soluble up to 1.5g/100mL at 25 °C. It is usually accessible as the monohydrated hydro bromide salt. However, some newer extended-release formulations contain Dextromethorphan bound to an ion-exchange resin based on polystyrene sulfonic acid (Picture 1).

Picture 1: Chemical structure of Dextromethorphan Hydro bromide.

Mechanism of Action

Dextromethorphan is a synthetic compound and acts as a dissociative anesthetic when taken in higher doses. Its mechanism of action is via multiple effects, plus actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist [2]. Dextromethorphan and its major metabolite, Dextrorphan, also act as NMDA receptor antagonist at high doses, which produces effects similar to other dissociative anesthetics such as ketamine and phencyclidine [3]. The metabolic pathway continues from dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan (Figure 1) [4].

Figure 1: Explains the metabolic pathway of the drug Dextromethorphan.

In one of the reported processes for the preparation of morphinan alkaloids, racemic hydroxy N- methyl morphinan is used as a starting material, an optically inactive isomer and is treated with tartaric acid for resolution to obtain selective one isomer (+) of morphinan. (PATENT- US2676177 (Roche, 1954, CHprior. 1949)) (Scheme 1).

Scheme 1: This scheme explains the reported procedure that uses a racemic hydroxy N- methyl morphinan as a starting material along with the use of solvents.

In a similar procedure reported in PATENT- CN102977021 A, Method for preparation of Dextromethorphan hydro bromide By Cui, Dapeng et al From Faming Zhuanli Shenqing, 102977021, 20 Mar 2013, Raney Nickel as a reducing agent is replaced by KBH4, thus, reducing the cost. Also, resolution is done with R-ibuprofen for the first time. Another advantage is the use of AlCl3 is adopted to replace H3PO4 to cyclize. Overall, it is a low cost, moderate reaction conditions, easy in operation and suitable for industrial production (Scheme 2).

Further, in the search for better preparation methods, which is easier, lesser preparation steps, cost effective, and also using chemicals that are easy to handle and can provide higher yields as well as purity, it has been found that the critical step of Grewe’s cyclization is reported in a paper titled, ‘A Novel synthesis of substituted 1-benzyloctahydroisoquinolines by acid-catalyzed cyclization of N-[2-(Cyclohex-1-enyl]-N-styryl formamides’ [5] (Scheme 3).

Scheme 2: Explains another reported procedure, where alternate reagents like KBH4, R-ibuprofen and AlCl3 have been used to refine the existing method of preparation of Dextromethorphan.

Scheme 3: Explains a reported procedure involving the preparation of Dextromethorphan that involves Grewe`s cyclization.

Scheme 4: Explains a reported procedure of Dextromethorphan preparation, where formylation was done before the cyclization step to improve the yield.

According to this paper, no cyclization of enamide was observed with Lewis acid catalyst (AlCl3, AlEtCl2, TiCl4), Two equivalents of BF3-Et2O was used, and complete conversion was observed. In all cyclization reactions, a side product is formed that is more polar than the octa hydroisoquinolines and N-formyl octa hydroisoquinolines synthesized from N-formyl- 2-phenylethylamines and benzaldehyde. Also, reduction of N-formaldehyde to N-methylated was done using LiAlH4. While going through literature, it was found that formylation before cyclisation avoids ether cleavage as a side reaction and higher yields were obtained than without N-substitution or N-methylation. In this patent, purification/resolution was done using the formation of Brucine salt (US3634429 (Jan 11, 1972) Morphinan derivatives and preparation there of (Scheme 4).

Experimental and Results

All the above-mentioned processes involve the use of solvents. So, in the existent investigation, an endeavor is explored to develop an alternate process wherein use of solvents can be avoided in the synthesis of Dextromethorphan (Scheme 5).

Scheme 5: Explains a greener preparation of Dextromethorphan using an Ionic Liquid.

Preparation of Dextromethorphan Hydrobromide using 1-butyl-3-methyl imidazolium acetate (Ionic liquid) as a solvent

I-step:

a) Stage-IA: In a flask, charge 1-butyl-3-methyl imidazolium acetate under nitrogen atmosphere. Charge (S)-Octa base under nitrogen atmosphere. Cool if required under nitrogen atmosphere. Charge Sodium methoxide solution in methanol under nitrogen atmosphere. Charge Methyl formate. Raise the temperature of the reaction mass to little reflux by using hot water not more than 55oC. Stir and maintain the reaction mass till reaction complies (2 hours). Concentrate the reaction mass u/v (Capacity of vacuum pump should be > 700 mm/Hg) till almost no solvent distills. To the concentrated reaction mass, charge toluene under nitrogen atmosphere and water extraction is done. The extracted toluene layer was concentrated to give N-Formyl octa base and is used as such.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 1) and (Picture 2).

Table 1: s- singlet, m-multiplet, br-broad.

Picture 2:

b) Stage-IB: In another flask, charge Ortho phosphoric acid (~ 85.0 % w/w). Charge Toluene and Raise the temperature of the reaction mass. Reflux and maintain over Dean stark apparatus to remove water azeotropically. Cool the reaction mass under nitrogen atmosphere and Charge Phosphorus pentoxide under nitrogen atmosphere. Reaction is highly exothermic. Charge 1-butyl-3-methyl imidazolium acetate. Slowly add N-formyl octa base and Raise the temperature of the reaction mass under nitrogen atmosphere. Stir and maintain the reaction mass at 65-70oC under nitrogen atmosphere till reaction complies. Concentrate the reaction mass under vacuum to remove toluene. To the concentrated mass, charge ethyl acetate under nitrogen atmosphere and stir. In another flask, charge water, Cool. Charge ethyl acetate reaction mixture reaction mass in to chilled water. Stir, settle and separate the layers. Repeat for back extraction. Wash the organic layer with water again and then a wash of 7% sodium bicarbonate solution is given. Concentrate the organic layer u/v till almost no solvent distills. Degas the concentrate u/v to remove traces of solvents.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 2) and (Picture 3)

Table 2: s- singlet, m-multiplet, br-broad.

Picture 3:

c) Stage-IC: To the concentrate mass, charge 1-butyl- 3-methyl imidazolium acetate and methanol under nitrogen atmosphere. Stir and slowly add sodium hydroxide solution Pre- Cooled ~15oC (Prepare by using 109 g Sodium hydroxide dissolved in 200ml Water). Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~15 hours). Concentrate the reaction mass u/v. To the concentrate mass, charge toluene under nitrogen atmosphere and water workup is done. The extracted toluene layer was concentrated to give N-Nordextromethorphan (Stage-IC).

m/z (M+H+) - 258

NMR chemical shift values tabulated below (Table 3) and (Picture 4):

Table 3: s- Singlet, m-multiplet, br-broad.

Picture 4:

d) Stage-ID: To the mixture of1-butyl-3-methyl imidazolium acetate and N-Nordextromethorphan (Stage-IC), slowly add Formic acid solution (Prepare by using 32.1g Formic acid diluted with 5.7ml water). Charge Formaldehyde solution. Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~2 hours). After the reaction is complete, Charge water and cool the reaction mass if required and then slowly add sodium hydroxide solution Pre-cool (< 15 oC) (Prepared by using 28.0g Sodium hydroxide dissolved in 140ml water), extracted the product into toluene, again charge water, cool, and slowly add Hydrobromic acid. Raise the temperature of the reaction mass to 70-80 oC and Stir and maintain to get clear solution. The organic and aqueous layers separated. Cool the Aqueous layer under stirring to get precipitate and further cooled to 3-6 oC and wash with pre-chilled water. Dry the solid under vacuum, to get Dextromethorphan hydro bromide.

m/z (M+H+) - 272

NMR chemical shift values tabulated below (Table 4) and (Picture 5):

Table 4: s- Singlet, d- doublet, m-multiplet, br-broad.

Picture 5:

a) 1H-1H coupling constants.

Discussion

As of today, chemical manufacturing process of APIs in pharmaceutical industry is handicapped without the use of chemical solvents. However, it is a scientifically known fact that solvents are dangerously damaging chemical entities, mainly of the following reasons:

a) Volatile nature of solvents.

b) Storage and handling risks.

c) Usage requirements in large scale.

Apart from their handling risks to human beings, they also cause significant saturation in chemical pollution levels in the environment; there has been constant research going-on in academic field as well as industries to find their suitable alternative [6].

Ionic liquids are one such alternative that has been found useful to substitute the commonly used bench solvents. Other than their obvious “solvent” property that have been discussed in various publications [7-10], they have also been found to catalyze certain type of reactions in which they participate [11-13]. Moreover, their complete recovery from the reaction is an easy job when juxtaposed with their volatile solvent counterparts. For this reason, an ionic liquid can be re-cycled for multiple batches of reactions.

Another unique property of ionic liquids is that they can be “tailor-made” to suit specific reaction types by playing around with the cation and anion part of them. They are called as “task-specific ionic liquids”. These tailored [14] and specially synthesized ionic liquids have more scope of their application in a chemical reaction than just acting as a green solvent.

Conclusion

A simple, efficient, eco-friendly synthetic route is developed involving the single-step synthesis of Dextromethorphan Hydrobromide that is high on convenience and also a cost-effective procedure. This process is best suitable for the preparation of Dextromethorphan Hydrobromide and is scalable in plant. This synthetic route using an ionic liquid adapts a cleaner chemistry that assures both risk-free handling and reduced environmental pollution, when scaled-up.

Acknowledgement

Our group would like to thank the Department of Scientific and Industrial Research India, Dr. Hari Babu (COO Mylan), Sanjeev Sethi (Chief Scientific Officer Mylan Inc ); Dr Abhijit Deshmukh (Head of Global OSD Scientific Affairs); Dr Yasir Rawjee {Head-Global API (Active Pharmaceutical Ingredients)}, Dr Sureshbabu Jayachandra (Head of Chemical Research) Mr Manoj Pananchukunnath (Head of Global Injectables Scientific Affairs, Product Development) Dr. Suryanarayana Mulukutla (Head Analytical Dept MLL API R & D) as well as analytical development team of Mylan Laboratories Limited for their encouragement and support. We would also like to thank Dr Narahari Ambati (AGC- India IP) & his Intellectual property team for their support.

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Lupine Publishers | Chloride-Induced Highly Active Catalyst for Methyl Esterification of Alcohols

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

In this work, a series of active Au/NiOx catalysts were successful to prepare by tracing the concentrations of chloride in the re-dispersed aqueous solutions. By characterizations, we found that the appropriate amount of residual chloride in Au catalyst would induce Au nanoparticles (Au NPs) to locate on the edges of NiOx particles, which resulted in the active Au/NiOx-9 sample. Fine control of chloride in the aqueous solution provides a new perspective to push for addressing the controllable preparation of active heterogeneous catalysts.

Keywords: Au catalyst, Preparation, Chloride, Esterification

Introduction

In recent decades, Au catalysts have received growing attentions and been widely applied in many important research fields [1], since good performance of Au catalysts was discovered [2]. However, the controllable preparation of highly active heterogeneous catalysts is still a longstanding challenge till now, especially Au catalysts. Many efforts have been devoted to this problem. The active site, structure and the quantum size effect of Au catalyst [3], active oxygen species of the support [4], suitable reducible oxide supports [5],and so on, have been extensively studied. Additionally, catalyst precursors, bases, pH value, aging time, and calcinations temperature are also crucial conditions [2,6]. Nevertheless, the controllable preparation of highly active Au catalyst is still difficult to realize even strictly following all above conditions. Chloride (usually as Cl-) is generally regarded as a poison for Au catalyst, Because of strong interaction of chloride and Au. We realized the reproducible preparation of Au/Fe2O3 catalyst for CO oxidation [7]. It is meaningful to explore whether this method can be applied to other catalysts and reactions or not. In this work, Methyl esterification of alcohols was chosen as model reaction. The controllable preparation of highly active Au/ NiOx catalyst was realized by tracing the concentrations of chloride in the re-dispersed aqueous solutions.

Experimental Details

Au/NiOx catalyst preparation

20ml Ni(NO3)36H2O (0.011 M) and 1.05 ml HAuCl4 (0.24M) were mixed together and were drop wise added into 60 ml Na2CO3 solution (0.31M) under vigorous stirring in 3h. The turbid liquid was divided into four sections and separation by centrifugation. Each section of the recovered precipitate was re-dispersed in different amount of deionised water and ultrasonically washed for 1h. The chloride concentration in the re-dispersed aqueous solution of each section was determined by CHI660D electrochemical workstation. Then, the solid was separated by centrifugation, dried at 80o C for 3h and calcined at 350 oC for 0.5 h to produce the catalyst sample, which was denoted as Au/NiOx-X, in which X suggested the chloride concentration in ppm.

Catalyst activity test

1mmol benzyl alcohol, 30 mg catalyst and 2 ml methanol were added into a glass tube. And then it was exchanged with oxygen and reacted at 60o C (1 atom, O2 balloon). After reaction, it was cooled to room temperature. Biphenyl was used as internal standard and a certain amount of ethanol were added into the reaction mixture up to 10mL for quantitative analysis by GC-FID (Agilent 7890A).

Results and Discussion

The catalytic activities of 15 Au/NiOx samples, which were prepared from the re-dispersed aqueous solutions with chloride concentrations in the range of 2 to 108 ppm, for esterification of benzyl alcohol were studied. According to the results shown in Figure 1, catalytic activity of Au/NiOx varied with the changing of chloride concentration. The yields of methyl benzoate were lower than 21% if the catalysts were prepared from aqueous solutions containing >22ppm chloride. More active catalysts were produced when the chloride concentrations were going down. The Au/ NiOx catalysts with the highest catalytic activity were prepared from aqueous solutions containing 8-13ppm chloride, the yield of methyl benzoate of catalyst Au/NiOx-9 was >99%. Surprisingly, the catalysts turned less active again when the chloride concentrations were < 8ppm. Typically, the yield of methyl benzoate was 20% with catalyst Au/NiOx-3.

Figure 1: The yield of methyl benzoatevs the chlorine concentration of the aqueous solution from which the catalyst samples were prepared.

Figure 2: HR-TEM (left) images and size distributions (right) of Au/NiOx-22 (a), Au/NiOx-9 (c), and Au/NiOx- 3(e).

TEM measurement results of Au/NiOx are shown in Figure 2. Their TEM images were similar and seemed amorphous. For the sample of Au/NiOx-22, the lattice of gold could be observed and wrapped in NiOx particle. For active Au/NiOx-9, the most of Au NPs connected with the edges of NiOx particles or the junctions of several NiOx particles [8]. In consideration of the best catalytic performance of this sample, this observation strongly supported the former results about active site in Au catalyst, i.e. the interface between Au and iron oxide [3]. It suggested that the appropriate amount of chloride might act as the linkage between Au NPs and the edges of NiOx particles to gain the active Au catalyst, For Au/ NiOx-22 and Au/NiOx-3, too much or less chloride was presented, the interaction of Au NPs and NiOx like Au/NiOx-9 decreased significantly. Accordingly, the catalytic activity lost sharply. By metering more than 150Au NPs, the mean diameters of Au NPs in samples Au/NiOx-3, Au/NiOx-9 and Au/NiOx-22were 4.1, 3.8 and 6.6 nm with 1.91, 1.84 and 3.06 standard deviations. The size distributions of Au NPs in Au/NiOx-3 and Au/NiOx-9 samples were extremely similar. The marked difference of catalytic activities of these two catalysts did not come from the size effect of Au particles, but the contact way of Au NPs and NiOx supports.

At present, there is still not sufficient evidence to explain the real role of chloride in the formation of Au catalysts. However, according to the known evidence, we can make some reasonable conjectures. Firstly, as pH value of the mother aqueous solution rises, chlorine in chloroauric acid is substituted by the hydroxyl. Au-Cl bond breaks and then small Au NPs form. Finally, chloride is adsorbed on the support NiOx as well as Au NPs. Due to the stronger interaction of chlorideon the edges than on planes of NiOx crystallites, after the ultrasonication and washing operations, chloride located on the edges of NiOx crystallites remains. As shown in Figure 3, it is this kind of residual chloride that induces Au NPs to anchor on the edges of NiOx crystallites.

Figure 3: The simple scheme of Au/NiOx catalysts.

Conclusion

In summary, by tracing the chloride concentrations in the re-dispersed aqueous solution, we successfully prepared active Au/NiOx catalyst for catalytic methyl esterification of alcohols. If the chloride concentration was not in the range of 8-13ppm, the catalytic activity dropped dramatically. These results indicated that the presence of appropriate amounts of residual chloride was beneficial to obtain highly active heterogeneous catalysts. This work can offer a new perspective to realize the controllable preparation of active heterogeneous catalysts.

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Lupine Publishers | Palauamine and Olympiadane Nano Molecules Incorporation into the Nano Polymeric Matrix (NPM) by Immersion of the Nano Polymeric Modified Electrode (NPME) as Molecular Enzymes and Drug Targets for Human Cancer Cells, Tissues and Tumors Treatment under Synchrotron and Synchrocyclotron Radiations

 Lupine Publishers | Journal of Organic & Inorganic Chemical Sciences

Abbrevations: NPM: Nano Polymeric Matrix; NPME: Nano Polymeric Modified Electrode; CEMs: Chemical Modified Electrodes; MWCNTs: Multi–Walled Carbon Nanotubes; CPE: Carbon Paste Electrode

Editorial

In the current editorial, we study Palau’amine and Olympiadane Nano molecules (Figures 1 & 2) incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations. In this regard, the development of Chemical Modified Electrodes (CEMs) is at present an area of great interest. CEMs can be divided broadly into two main categories; namely, surface modified and bulk modified electrodes. Methods of surface modification include adsorption, covalent bonding, attachment of polymer Nano films, etc. Polymer Nano film coated electrodes can be differentiated from other modification methods such as adsorption and covalent bonding in that they usually involve multilayer as opposed to monolayer frequently encountered for the latter methods. The thicker Nano films imply more active sites which lead to larger analytical signals. This advantage coupled with other, their versatility and wide applicability, makes polymer Nano film modified electrodes particularly suitable for analytical applications [1–27].

Figure 1: Molecular structure of Palau’amine Nano molecules.

Figure 2: Molecular structure of Olympiadane Nano molecules.

Electrochemical polymerization offers the advantage of reproducible deposition in terms of Nano film thickness and loading, making the immobilization procedure of a metal–based electro catalyst very simple and reliable for Palau’ amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations. Also, it must be notice that the nature of working electrode substrate in electro preparation of polymeric Nano film is very important, because properties of polymeric Nano films depend on the working electrode anti–cancer Nano materials. The ease and fast preparation and of obtaining a new reproducible surface, the low residual current, porous surface and low cost of Multi–Walled Carbon Nanotubes (MWCNTs) paste are some advantages of Carbon Paste Electrode (CPE) over all other solid electrodes [28–92].

On the other hand, it has been shown that, macrocyclic complexes of Palau’amine and Olympiadane Nano molecules– encapsulating Carbon nanotubes are interest as modifying agents because in basic media Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes redox centers show high catalytic activity towards the oxidation of small organic anti-cancer Nano compounds. The high–valence species of Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes seem to act as strong oxidizing agents for low-electroactivity organic substrates. 1,2–Dioxetane (1,2– Dioxacyclobutane), 1,3–Dioxetane (1,3– Dioxacyclobutane), DMDM Hydantoin and Sulphobe as the anti–cancer organic intermediate products of methanol oxidation as well as formic acid, is important to investigate its electrochemical oxidation behavior in Palau’ amine and Olympiadane Nano molecules-encapsulating Carbon nanotubes incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations [93–110].

In this editorial, we decided to combine the above mentioned advantageous features for the aim of Palau’ amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations. Furthermore, in this editorial, we prepared poly Nano films by electropolymerization at the surface of Multi-Walled Carbon Nanotubes (MWCNTs) paste electrode. Then, Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes were incorporated into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) in a solution. The modifier layer of Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes at the electrode surface acts as a Nano catalyst for the treatment of human cancer cells, tissues and tumors under synchrotron and synchrocyclotron radiations. Suitability of this Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes–modified polymeric Multi–Walled Carbon Nano tubes (MWCNTs) paste electrode toward the electrocatalytic treatment of human cancer cells, tissues and tumors under synchrotron and synchrocyclotron radiations in alkaline medium at ambient temperature was investigated [111– 153].

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Lupine Publishers | 3D Printing of Pharmaceutical Drug Delivery Systems

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

Three-dimensional printing (3DP) enables the development of diverse geometries through computer aided design using different techniques and materials for desired applications such as pharmaceutical drug delivery medicine. The FDA approval (2015) of printed-medicine opens up an unprecedented opportunity for the discovery of new compounds and technologies for the pharmaceutical industry development. This report shows some advantages, limitations, challenges and perspectives in concerning to 3DP of pharmaceutical grade formulations and polymers used for drug delivery systems.

Introduction

Drug delivery refers to approaches, systems, technologies and formulations for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect. The concept of drug delivery has greatly evolved over the years from immediate-release oral dosage forms to targeted-release drug delivery systems. Indeed, the necessity of controlling the drug release profile to modulate the absorption, the distribution, the metabolization and the elimination of the drug rapidly appeared as a key factor for improving product efficacy and safety as well as to increase the compliance of the patients [1]. In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer [2].

Three dimensional printing (3DP) technology is a novel technique for rapid prototyping, which constructs solid objects by deposition of several layers in sequence. The introduction and application of 3D printing have promoted enormous innovations in many diverse fields, including aerospace industry, architecture, tissue engineer, biomedical research and pharmacy. It seems that 3D printing technology will lead a new epoch of the next industrial revolution based on its versatility and diversity. Along with development and progress in science and technology, the 3D printing technology gets mature enough so that anyone can apply it with open-source software at a relative lower material cost [3]. The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and it's potential yet to be fully explored [4].

3DP is gaining increasing attention in pharmaceutical formulation development as an effective strategy to overcome some challenges of conventional pharmaceutical unit operations. For instance, the conventional manufacturing unit operation involving milling, mixing, granulation and compression can result in disparate qualities of the final products with respect to drug loading, drug release, drug stability and pharmaceutical dosage form stability [5,6]. 3D printing technology has enabled unprecedented flexibility in the design and manufacturing of complex objects, which can be utilized in personalized and programmable medicine [7]. In this report are shown some advantages, limitations, challenges and perspectives of 3D printing in the elaboration of drug delivery systems.

Advantages and Limitations

Various techniques for 3D printing, such as fused deposition modeling (FDM), binder deposition, inkjet printing, material jetting, powder bed fusion, photopolymerization, pen-based 3D printing and molding, have been reported in the literature [8,9]. Fused Deposition Modeling (FDM) 3D printing has been recently attracted increasing research efforts towards the production of personalized solid oral formulations. However, commercially available FDM printers are extremely limited with regards to the materials that can be processed to few types of thermoplastic polymers, which often may not be pharmaceutically approved materials nor ideal for optimizing dosage form performance of poor soluble compounds [10]. Such a technique holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation. Challenges in this field are mainly related to the paucity of adequate filaments composed of pharmaceutical grade materials, which are needed for feeding the FDM equipment [11] (Figure 1).

Figure 1: Schematic view of the different 3DP techniques used to fabricate drug delivery systems.

Source [12] From the many types of 3DP available, stereolithographic (SLA) printing offers the unique advantage of being able to fabricate objects by cross-linking resins to form networked polymer matrices. Because water can be entrapped in these matrices, it is possible in principle to fabricate pre-wetted, drug-loaded hydrogels and devices [13].

Table 1: Current 3DP technologies and pharmaceutical formulations for drug delivery.

More information in concerning to these technologies and pharmacology is present in the studies of Jassim-Jaboori & Oyewumi (14), Konta et al. [15], and Mauvi et al. [16].

Challenges and Perspectives

The technological advancements in the pharmaceutical field are constantly improving and provide various possibilities for meeting the needs of personalized drug therapy. The three-dimensional (3D) printing technology has endless potential in the fabrication of patient-specific drug delivery devices (DDD) and dosage forms as the technological development is progressing. Moreover, the rapidly evolving research on 3D printed DDD has enabled.com to determine several challenges related to the manufacturing and marketing of personalized drug delivery systems. The 3D printing has enabled the fabrication of prototypes of DDD with varying complexity and shows that customization of drug products is possible. There is potential to improve patient-specific drug therapies of the future using printing technologies. The technological advancements, new scientific concepts, interdisciplinary work and defined regulatory guidelines will continue to support and strengthen the prospects of 3D printing as an option in the manufacture of medical products [17]. Three-dimensional printing (3DP) is a unique prototyping technology that has advanced over the past 35 years and has the great potential to revolutionize the field of drug delivery with its inherent advantages of customizability and the ability to fabricate complex solid dosage forms with high accuracy and precision. 3DP can fabricate solid dosage forms with variable densities and diffusivities, complex internal geometries, multiple drugs and excipients. 3DP can successfully address the issues relating to the drug delivery of poorly water-soluble drugs, peptides, potent drugs and the release of multi-drugs, etc. However, there are some problems that restrict the applications of 3DP in commercial market, such as the selections of suitable binders, excipients and the pharmaco-technical properties of final products. Further advancement in process performance is required to overcome these issues where 3DP technology can be successfully combined with novel drug delivery system (NDDS) [18].

3D printing encompasses a range of differing techniques, each involving advantages and open issues. Particularly, solidification of powder, extrusion, and stereo lithography have been applied to the manufacturing of drug products. The main challenge to their exploitation for personalized pharmacologic therapy is likely to be related to the regulatory issues involved and to implementation of production models that may allow to efficiently turn the therapeutic needs of individual patients into small batches of appropriate drug products meeting preset quality requirements [19].

Three-dimensional printing has become a useful and potential tool for the pharmaceutical sector, leading to personalized medicine focused on the patients' needs. It offers numerous advantages, such as increasing the cost efficiency and the manufacturing speed, since a rapid prototyping (RP) can be done in a matter of minutes. However, there is still a significant barrier to ensure that 3D printed medicines have the same efficacy, safety, and stability as the pharmaceuticals conventionally manufactured by the Pharmaceutical Industry. Regarding the establishment of guidelines, laws, quality systems and safety of use and consumption of 3D printed medicines, it is a great challenge for the regulatory authorities entailing great obstacles, given the traditional requirements by the pharmaceutical sector [13].

The use of various types of printing technologies offer potential solutions for personalized medicine and tailored dosage forms to meet the needs of individual treatments of the future. Many types of scenario for printed dosage form exist and the concepts include, on the simplest level, accurately deposited doses of drug substances. In addition, computer design allows endless opportunities to create suitable geometries with tailored functionality and different levels of complexity to control the release properties of one or multiple drug substances. It will take some time to convert these technological developments in printing to better treatments for patients, because challenges exist. However, printing technologies are developing fast and have the potential to allow the use of versatile materials to manufacture sophisticated drug-delivery systems and bio functional constructs for personalized treatments [20].

3D printing technology can handle complex internal structure such as internal walls, hollow channels, porosity, multiple material regions and multiple drug distributions. This is a feature traditional pharmaceutical manufacturing processes do not share, which ensures feasibility of realizing rapid release, sustained release, controlled release, multiple drug delivery system and personalized medicine based on structure design [21]. Indeed, drug delivery from 3-dimensional (3D) structures is a rapidly growing area of research. It is essential to achieve structures wherein drug stability is ensured, the drug loading capacity is appropriate and the desired controlled release profile can be attained. Attention must also be paid to the development of appropriate fabrication machinery that allows 3D drug delivery systems (DDS) to be produced in a simple, reliable and reproducible manner [22].

Findings

It is evidenced that through its versatility, speed of production and precision, the use of three-dimensional printing for the elaboration and distribution of controlled drugs plays a key role in the current pharmaceutical industry, considering that drugs can be designed according to the patient's need. The fused deposition modeling (FDM) technique and hot melt extrusion (HME) of filaments for 3DP still excels in relation to the other printing techniques, such as binder deposition, inkjet printing, material jetting, powder bed fusion, photopolymerization, pen-based 3D, printing and molding have been gaining more and more space. The use of3DP in pharmaceutical formulation development is an effective strategy to overcome challenges of conventional pharmaceutical unit operations, since the conventional manufacturing operation can result in disparate qualities of the final products with respect to drug loading, drug release, drug stability and pharmaceutical dosage form stability. 3DP offers significant potential benefits in the field of drug delivery and pharmaceutical/medical device manufacture.

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Lupine Publishers | Synthesis and Bioactivity of Novel Tri-Heterocyclic Molecules: {4-[3-({[5-(Substituted)-1,3,4-Oxadiazol-2-Yl] SulfanyljMethyl) Benzoyl] -1 -Piperazinyl} (2-Furyl)Methanones

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

In the presented investigation, some novel tri-heterocyclic benzamides, 8a-g, were synthesized in several steps. First, the electrophilic benzamide, {4-[3-(chloromethyl)benzoyl]-1-piperazinyl}(2-furyl) methanone (3), was synthesized by the reaction of 2- Furoyl-1-piperazine (1) and 3-chloromethylbenzoyl chloride (2). In second series of steps, different carboxylic acids, 4a-g, were refluxed with ethanol and conc. sulfuric acid to form esters, 5a-g. These esters were further refluxed with N₂H₄.H₂O in methanol solution to acquire acid respective hydrazides, 6a-g. These hydrazides were cyclized by refluxing with KOH, ethanol and CS₂ into corresponding 1,3,4-oxadiazoles, 7a-g. In the final step, the electrophile, 3, was coupled with synthesized 1,3,4-oxadiazoles, 7a-g, in acetonitrile and potassium carbonate to acquire the targeted tri-heterocyclic molecules, 8a-g. The structural characterization of these novel compounds 8a-g was done by IR, ¹H-NMR, ¹³C-NMR and EI-MS spectral data. These synthesized molecules were subjected to antibacterial and enzyme inhibitory and cytotoxicity evaluation. Among the series, 8b exhibit good enzyme inhibition whereas 8c exhibited good antibacterial and antifungal potential against B. subtilis, E. coli and A. flavus strains, respectively. Most of the molecules possessed moderate cytotoxicity and hence these can be utilized as possible therapeutic agents.

Keywords: Tri-Heterocyclic; ¹H-NMR; ¹³C-NMR; EI-MS; Hemolytic Activity; Enzyme Inhibition; Antibacterial; Antifungal activity

Introduction

Ox diazole is a heterocyclic five membered ring bearing two nitrogen atoms and one oxygen atom. It has four different isomers among these four different isomers, 1,3,4-oxadiazole has been synthesized in the presented work and subjected to formation of some new derivatives [1]. A lot of derivatives of 1,3,4-oxadiazole has been synthesized by substituting at second and fifth positions of the ring. They undergo a variety of organic reactions such as electrophonic substitution, nucleophilic substitution, thermal and photochemical reactions and hence act as a medicinal backbone on which a number of valuable molecules have been constructed [2] . A broad spectrum of biological activities reported for different substituted 1,3,4-oxadiazole derivatives include anticonvulsive [3]. Muscle relaxant [4]. Herbicidal, antimicrobial [5]. Insecticidal [6]. Antibacterial, anti-inflammatory [7,8]. Analgesic, hypoglycemic [9,10]. Anti-Parkinson, anti-mitotic, anticancer [11]. Anti-tubercular [12]. Tranquilizing, anti-proliferative, antifungal [13]. Anti-HIV, anti-depressive etc [14]. Piperazine nucleus is one of the most important heterocycles exhibiting remarkable pharmacological activities. Piperazine is a heterocyclic compound, containing nitrogen atoms at opposite positions in six membered ring [15]. The piperazine scaffold has been classified as a privileged structure and is frequently found in biologically active compounds across a number of different therapeutic areas [16]. This motif is found in drug candidates displaying anti-depressant, analgesic, anti- allergenic, antibacterial, anti-cancer, anti-psychotic, anti-migraine, gastrointestinal agent and cardio tonic agent [17-23]. Thus, it appears that the piperazine core acts as a privileged structural element for the construction of bioactive molecules [24]. In order to find new drug candidates, the piperazine ring is encompassed in the new synthesized compounds along with 1,3,4-oxadizole. The coupling of multiple functionalities was considered to boost up the bioactivity potential of resulting molecules. The presented work covers synthesis of new compounds having different bioactive moieties like piperazine, 1,3,4-oxadiazole and carbamate. The antibacterial, enzyme inhibition and hemolytic potential have also been demonstrated for all the synthesized molecules. The present work was aimed to synthesize new molecules in order to evaluate their bioactivity potential against certain bacterial strains and enzymes.

Experimental

Chemistry

Purity was checked on thin layer chromatography (TLC) on pre-coated silica gel G-25-UV254 plates using different percentage of ethyl acetate and n-hexane giving single spot. Griffin and George melting point apparatus was used to record the melting points of the synthesized compounds by open capillary tube and were uncorrected. Jasco-320-A spectrophotometer was used for the IR spectra (wave number in cm-1). 1H-NMR spectra were recorded in CDCl3 on a Bruker spectrometers operating at 600 MHz. 13C-NMR spectra were recorded in CDCl₃ on a Bruker spectrometers operating at 150MHz. Chemical shifts were recorded in ppm. Mass spectra (EI-MS) were taken on a JMS-HX-110 spectrometer, with complete data system.

General Synthesis of {4-[3-(chloromethyl)benzoyl]-1- Piperazinyl}(2-furyl)Methanone (3)

1-(2-Furoyl)piperazine (12.8mmol; 1) was taken in an iodine flask (250mL) containing 15.0mL of distilled water and 10 % Na₂CO₃ solution to adjust pH at 9-10. Then equimolar 3-chloromethylbenzoyl chloride (2) was added drop wise to the reaction medium in 2-5min. After complete addition, the iodine flask was vigorously shaken (manually) and then set to stir at room temperature for 4 hours till the formation of solid precipitates. The progress of reaction was monitored by thin layer chromatography (TLC) till single spot. The obtained precipitates were filtered, washed with distilled water and dried to yield the titled electrophile, 3.

Procedure for the synthesis of ethyl carboxylates (5a-g)

Carboxylic acids (50mmol; 4a-g) were refluxed for 3-4 hrs with 40mL EtOH in a 250mL round bottom flask in the presence of conc. H2SO4 (0.5mL/g acid). After maximal completion by TLC, excess water was added and pH was adjusted to 8-10 by aq. Na₂CO₃ soln (10%). The title compounds, 5a-g, were extracted by chloroform.

Procedure for the synthesis of carbohydrazides (6a-g)

Compounds 5a-g (40mmol) and N2H4.H₂O (40mmol) were refluxed for 4-6 hrs in 25mL MeOH in a 100mL RB flask. After final TLC, excess water was added to acquire precipitates, 6a-g, which was separated by filtration.

General procedure for the synthesis of 5-substituted- 1,3,4-oxadiazol-2-thiols (7a-g)

Compounds 6a-g (30mmol) were refluxed for 0.5 hr with solid KOH (30mmol) in 45mL EtOH in a 100mL RB flask. Then CS2 (60mmol) was added and further refluxed for 3-6 hrs. After final TLC, excess water was added followed by conc. HCl to adjust pH of 2. The mixture was left for 3 hrs for precipitation. Precipitates, 7a-g, were collected through filtration and washed with water

General synthesis of tri-heterocyclic molecules (8a-g)

The respective 5-substituted-1,3,4-oxadiazol-2-thiol (24mmol; 7a-g, one in each reaction) was dissolved in acetonitrile (20-30mL) in 100mL round bottom flask. Then solid K2CO₃ (12mmol) was added. The mixture was refluxed for half an hour and then the equimolar (24mmol) the electrophile, 3, was added. The mixture was further refluxed for 4-5 hours. Thin layer chromatography was carried out to check the reaction completion. Distilled water was added to the reaction mixture to acquire the precipitates. Precipitates were filtered, washed and dried to get the titled compounds, 8a-g.

4-[3-({[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}methyl)benzoyl]-1-piperazinyl}(2-furyl) methanone (8a).

Light brown liquid; yield: 84%; Molecular formula: C₂₅H₂₁ClN₄O₄S; molecular mass: 508 g/mol; IR (KBr, υ_max cm^-1): 3411 (N-H), 3073 (Ar C-H), 2880 (R C-H), 1654 (C=O), 1582 (Ar C=C), 1203 (C-O-C), 1106 (C-N-C), 658 (C-S); 1H-NMR (600 MHz, CDCl₃, δ in ppm): 5 7.96 (d, J = 1.6 Hz, 1H, H-2"), 7.57 (dist. d, J = 1.5 Hz, 1H, H-5), 7.52 (d, J = 8.7 Hz, 1H, H-6”), 7.49-7.46* (m, 4H, H-3””, H-4””, H-5”" & H-6"”), 7.42 (t, J = 7.5 Hz, 1H, H-5"), 7.37 (dt, J = 1.5, 6.1 Hz, 1H, H-4"), 7.07 (d, J = 2.5 Hz, 1H, H-3), 6.50 (dd, J = 1.6, 3.3 Hz, 1H, H-4), 4.51 (s, 2H, H-8"), 3.84 (br s, 4H, H-3' & H-5'), 3.50 (br s, 4H, H-2' & H-6'); ¹³C-NMR (150 MHz, CDCl₃, δ in ppm): 170.04 (C-7''), 166.00 (C-5'''), 163.40 (C-2'''), 159.21 (C-6), 147.60 (C-2), 143.95 (C-5), 136.52 (C-3"), 135.57 (C-1”), 131.77 (C-1"”), 130.77 (C-2''''), 129.21 (C-4''''), 129.08 (C-3'''') 128.12 (C-5''''), 126.92 (C- 6’”’), 126.68* (C-4” & C-5”), 126.64 (C-2”), 123.46 (C-6"), 117.10 (C-3), 111.47 (C-4), 45.50* ( C-2’, C-3’, C-5' & C-6'), 36.21 (C-8"); EI-MS (m/z): 510 [M ⁺ 2]⁺, 508 [M]⁺, 440 [C₂₁H₁₆ClN₄O₃S•⁺, 411 [C₂₀H1₅ClN₄O₂S]⁺, 329 [C₁₆H₉ClN₂O₂S]⁺, 262 [C₁₂H₇ClN₂OS•⁺, 246 [C₁₃H₁₄N₂O₂•⁺,179 [C8H₄ClN₂O]•⁺, 179 [C₉H₁₁N₂O₂], 151[^C8^H9NO₂]⁺, 95 [C₅H₃O₂]⁺.

{4-[3-({[5-(3-Aminophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}methyl)benzoyl]-1-piperazinyl}(2-furyl) methanone (8b).

Light brown liquid; yield: 81%; Molecular formula: C₂₅H₂₃N₅O₄S; molecular mass: 489 g/mol; IR (KBr, υ_max cm^-1): 3413 (N-H), 3071 (Ar C-H), 2886 (R C-H), 1658 (C=O), 1580 (Ar C=C), 1203 (C-O-C), 1106 (C-N-C), 653 (C-S); 1H-NMR (600 MHz, CDCl₃, δ in ppm): δ 7.91 (d, J = 7.9 Hz, 1H, H-4”’’), 7.57 (s, 1H, H-2’”’), 7.56 (d, J = 1.5 Hz, 1H, H-2”), 7.54 (d, J = 8.0 Hz, 1H, H-6), 7.47 (d, J = 7.4 Hz, 1H, H-6”), 7.43 (br s, 1H, H-5), 7.42 (t, J = 7.5 Hz, 1H, H-5”"), 7.39-7.37* (m, 2H, H-4" & H-5” ), 7.06 (d, J = 2.5 Hz, 1H, H-3), 6.48 (br s, 1H, H-4), 4.52 (s, 2H, H-8"), 3.85 (br s, 4H, H-3' & H-5' ), 3.50 (br s, 4H, H-2' & H-6'); ¹³C-NMR (150 MHz, CDCl₃, δ in ppm): 170.08 (C-7"), 166.06 (C-5’”), 163.48 (C-2’”), 159.25 (C-6), 147.69 (C-2), 143.91 (C-5), 136.57 (C-3”), 135.50 (C-1"), 132.08 (C-3’”’), 131.70 (C-1""), 130.73 (C-2''''), 129.21 (C-4'''), 128.12 (C-5''''), 126.92 (C-6''''), 126.64 (C-2"), 126.62* (C-4” & C-5"), 123.45 (C-6"), 117.10 (C-3), 111.45(C-4), 45.51*( C-2', C-3', C-5' & C-6'), 36.21(C-8"); 489 [M]⁺, 421 [C₂₁H₁₉N₅O₃S]⁺ 392 [C₂₀H₁₈N₅O₂S]⁺, 310 [C₁₆H₁₂N₃O₂S]⁺, 246 [C₁₃H₁₄N₂O₃]⁺, 243 [C₁₂H₉N₃OS]•⁺,179 [C₉H₁₁N₂O₂]•⁺, 161 [C₈H₇N₃O]⁺, 151 [C₈H₉NO₂]⁺, 95 [C₅H30₂]⁺.

{4-[3-({[5-(3-Nitrophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}methyl)benzoyl]-1-piperazinyl}(2-furyl) methanone(8c).

Light brown liquid; yield: 86%; Molecular formula: C₂₅H₂₃N₅0₄S; molecular mass: 519 g/mol; IR (KBr, υ_max cm^-1): 3412 (N-H), 3070 (Ar C-H), 2887 (R C-H), 1653 (C=O), 1580 (Ar C=C), 1205 (C-O-C), 1107 (C-N-C), 652 (C-S 1H-NMR (600 MHz, CDCl3, δ in ppm): 5 8.35 (d, J = 2.0 Hz, 1H, H-2’”’), 8.17 (d, J = 6.9 Hz, 1H, H-6’’”), 7.83 (br s, 1H, H-2''), 7.59-7.53* (m, 1H, H-4'''' & H-5''''), 7.52 (br s, 2H, H-5), 7.48-7.43* (m, 2H, H-4’’ & H-5”), 7.07 (d, J = 3.2 Hz, 1H, H-3), 6.51 (dd, J = 1.7, 3.4 Hz, 1H, H-4), 4.55 (s, 2H, H-8”), 3.84 (br s, 4H, H-3’ & H-5' ), 3.51 (br s, 4H, H-2' & H-6'); ¹³C-NMR (150 MHz, CDCl³, δ in ppm): 169.96 (C-7’’), 165.18 (C-5’’’), 164.23 (C-2’’’), 159.22 (C-6), 149.53 (C-3''''), 147.61 (C-2), 143.97 (C-5), 136.20 (C-3''), 135.67 (C-1’’), 130.79 (C-6’’”), 129.25 (C-5”’’), 128.88 (C-4’’), 128.78 (C- 5’’), 128.44 (C-1’’”), 128.17 (C-2’’), 127.54 (C-6’’), 126.09 (C-4’”’), 125.49 (C-2’”’), 117.21 (C-3), 111.53 (C-4), 48.00* ( C-2', C-3', C-5’ & C-6'), 36.21 (C-8”); EI-MS (m/z): 519 [M]⁺, 451 [[C₂₁H₁₉N₅O₃S]•⁺ 422 [C₂₀H₁₈N₅O₂S]⁺, 340 [C₁₆H₁₂N₃O₂S]•⁺,, 273 [C₁₂H₉N₃OS]•⁺, 246 [C₁₃H₁₄N₂O₃]•⁺ 191 [C₈H₅N₃O₃]⁺, 179 [C₉H₁₁N₂0₂]⁺, 151 [C₈H₇N₃O]⁺, 95 [C₅H₃0₂]⁺.

{4-[3-({[5-(4-Methylphenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}methyl)benzoyl]-1-piperazinyl}(2-furyl) methanone (8d).

Black brown liquid; yield: 88%; Molecular formula: C₂₆H₂₄N₄0₄S; molecular mass: 488 g/mol; IR (KBr, υ_max cm^-1): 3411 (N-H), 3074 (Ar C-H), 2880 (R C-H), 1658 (C=O), 1583 (Ar C=C), 1209 (C-O-C), 1109 (C-N-C), 660 (C-S); 1H-NMR (600 MHz, CDCl3, δ in ppm): 5 7.86-7.83 (m, 1H, H-2’’), 7.55 (d, J = 8.6 Hz, 1H, H-6’’), 7.53-7.52 (m, 2H, H-2’”’ & H-6’’”), 7.49 (br s, 1H, H-5), 7.42 (t, J = 7.5 Hz, 1H, H-5’’), 7.37-7.36 (m, 1H, H-4’’), 7.33 (d, J = 6.0 Hz, 2H, H-3”’’ & H-5”’’), 7.07 (d, J = 3.4 Hz, 1H, H-3), 6.50 (dd, J = 1.8, 3.4 Hz, 1H, H-4), 4.50 (s, 2H, H-8’’), 3.84 (b s, 4H, H-3' & H-5'), 3.39 (br s, 4H, H-2' & H-6'), 2.39 (s, 3H, H-7””); ¹³C-NMR (150 MHz, CDCl₃, δ in ppm): 170.06 (C-7’’), 166.16 (C-5’’’), 163.08 (C-2’’’), 159.22 (C-6), 147.57 (C-2), 143.97 (C-5), 142.39 (C-3’’), 136.58 (C-1’’), 136.34 (C-4’’’’), 130.77 (C- 4’’), 130.38 (C-5’’), 129.20 (C-2’’’’ & C-6’’’’), 128.10 (C-3’’’’ & -5’’’’), 127.84 (C-2’’), 126.88 (C-6’’), 120.71 (C-1’”’), 117.09 (C-3), 111.52 (C-4), 46.50* ( C-2', C-3', C-5' & C-6'), 36.21 (C-8’’), 22.58 (C-7’”’); EI-MS (m/z): 488 [M]⁺, 420 [C₂₂H₂₀N₄0₃S]•⁺ 391 [C₂₁H₁₉N₅0₃]•⁺, 309 [C₁₇H₁₃N₂O₂S]⁺, 246 [C₁₃H₁₄N₂0₃]⁺ 242 [C₁₃H₁₄N₂0₃]•⁺ 179 [C₉H₁₁N₂0₂]⁺, 160 [C₉H₁₁N₂0₂]⁺, 151 [C₈H₇N₃O]⁺, 95 [C₅H₃0₂]⁺.

{4-[3-({[5-(4-Hydroxyphenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}methyl)benzoyl]-1-piperazinyl}(2-furyl) methanone (8e).

Light brown liquid; yield: 85%; Molecular formula: C₂₅H₂₃N₅0₄S; molecular mass: 490 g/mol; IR (KBr, υ_max cm^-1): 3075 (Ar C-H), 2889 (R C-H), 1654 (C=O), 1585 (Ar C=C), 1201 (C-O-C), 1109 (C-N-C), 655 (C-S); 1H-NMR (600 MHz, CDCl3, δ in ppm): 5 7.71 (d, J = 8.3 Hz, 2H, H-2’’’’ & H-6’’’’), 7.53 (br s, 1H, H-2’’), 7.52 (br s, 1H, H-5), 7.46 (d, J = 6.1 Hz, 1H, H-6’’), 7.40 (t, J = 7.6 Hz, 1H, H-5”), 7.33 (d, J = 7.4 Hz, 1H, H-4’’), 7.04 (d, J = 3.4 Hz, 1H, H-3), 6.86 (d, J = 8.4 Hz, 2H, H-3’”’ & H-5”’’), 6.47 (dd, J = 1.3, 3.0 Hz, 1H, H-4), 4.43 (s, 2H, H-8’’), 3.82 (br s, 4H, H-3’ & H-5’), 3.46 (br s, 4H, H-2’ & H-6’); ¹³C-NMR (150 MHz, CDCl₃, δ in ppm): 170.25 (C-7’’), 166.30 (C-5’’’), 162.21 (C-2’’’), 159.33 ³(C-6), 147.25 (C-2), 144.21 (C-5), 136.82 (C-3’’), 135.23 (C-1’’), 130.86 (C-4’’), 129.23 (C-5”), 128.54 (C-3”’’ & C-5’”’), 128.08 (C-6’’), 126.75 (C-1”’’), 161.05 (C-4”’’), 117.34 (C-3), 116.48 (C-2’’” & C-6’’’’), 114.25 (C-2”), 111.59 (C-4), 45.49* ( C-2', C-3', C-5’ & C-6'), 36.20 (C-8’’); EI-MS (m/z): 490 [M]⁺, 422 [C₆H₂N₂]⁺ 393 [C₆H₂N₂]⁺, , 246 [C₁₃H₁₄N₂O₃]•+ 244 [C₆H₂N₂]^•+ 179 [C₆H₂N₂]⁺, 161 [C₆H₂N₂]⁺, 151 [C₆H₂N₂]⁺, 118 [C₆H₂N₂]⁺ 95 [C₅H₃O₂]⁺

{4-[3-({[5-(2,4-Dichlorophenyl)-1,3,4-oxadiazol-2- yl]sulfanyl}methyl)benzoyl]-1-piperazinyl}(2-furyl) methanone (8f).

Light brown liquid; yield: 85%; Molecular formula: C₂₅H₂₃N₅O₄S; molecular mass: 542 g/mol; IR (KBr, υ_max cm^-1): 3414 (N-H), 3070 (Ar C-H), 2882 (R C-H), 1659 (C=O), 1579 (Ar C=C), 1198 (C-O-C), 1113 (C-N-C), 659 (C-S); 1H-NMR (600 MHz, CDCl₃, δ in ppm): 5 7.86 (d, J = 1.6 Hz, 1H, H-2’’), 7.59-7.51* (m, 2H, H-5’’’’ & H-6’’’’ ), 7.55 (dist. d, J = 1.6 Hz, 1H, H-5), 7.51 (d, J = 8.7 Hz, 1H, H-6’’), 7.45 (t, J = 7.5 Hz, 1H, H-5’’), 7.49 (s, 1H, H-3’’’’), 7.32 (dt, J = 1.5, 6.1 Hz, 1H, H-4’’), 7.09 (d, J = 2.5 Hz, 1H, H-3), 6.50 (dd, J = 1.5, 3.2 Hz, 1H, H-4), 4.50 (s, 2H, H-8’’), 3.88 (br s, 4H, H-3' & H-5'), 3.48 (br s, 4H, H-2’ & H-6’); ¹³C-NMR (150 MHz, CDCl₃, δ in ppm): 170.03 (C-7’’), 166.05 (C-5’’’), 163.48 (C-2’’’), 159.22 (C-6), 147.65 (C-2), 143.99 (C-5), 137.89 (C-4’”’), 136.58 (C-3’’), 135.59 (C-1”), 134.90 (C-1’’”), 133.72 (C-6’”’), 131.21 (C-5”’’), 129.44 (C-2’’”), 127.65 (C- 3’”’) 126.67* (C-4” & C-5’’), 126.62 (C-2’’), 123.49 (C-6”), 117.10 (C-3), 111.43 (C-4), 48.55* ( C-2', C-3', C-5' & C-6'), 36.22 (C-8’’); EI- MS (m/z): 546 [M ⁺ 4]⁺, 544 [M ⁺ 2]⁺, 542 [M]⁺, 474 [C₅H₃O₂]•⁺ 445 [C₅H₃O₂]⁺, 363 [C₅H₃O₂]⁺, 296 [C₅H₃O₂]^•+ 246 [C₅H₃O₂]^•+, 213 [C₅H₃O₂]⁺, 179 [C₅H₃O₂]⁺, 151 [C₅H₃O₂]⁺, 118 [C₆H₂N₂O]⁺, 95 [C₅H₃O₂]⁺.

{4-[3-({[5-(3,5-Dinitrophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}methyl)benzoyl]-1-piperazinyl}(2-furyl) methanone (8g).

Light brown liquid; yield: 84%; Molecular formula: C₂₅H₂₀N₆O₈S; molecular mass: 564 g/mol; IR (KBr, υ_max cm^-1): 3417 (N-H), 3068 (Ar C-H), 2889 (R C-H), 1650 (C=O), 1584 (Ar C=C), 1206 (C-O-C), 1107 (C-N-C), 652 (C-S); 1H-NMR (600 MHz, CDCl₃, δ in ppm): 5 8.07 (s, 1H, H-4’”’), 7.59 (d, J = 6.3 Hz, 2H, H-2’”’ & H-6’”’), 7.53 (s, 1H, H-2”), 7.49 (br s, 1H, H-5), 7.46 (d, J = 7.4 Hz, 1H, H-6"), 7.43 (t, J = 7.7 Hz, 1H, H-5’’), 7.34 (d, J = 7.0 Hz, 1H, H-4”), 7.07 (d, J = 4.2 Hz, 1H, H-3), 6.51 (br s, 1H, H-4), 4.48 (s, 2H, H-8”), 3.86 (br s, 4H, H-3' & H-5'), 3.66 (br s, 4H, H-2' & H-6'); ¹³C-NMR (150 MHz, CDCl₃, δ in ppm): 170.09 (C-7”), 166.05 (C-5’’’), 163.45 (C-2’”), 159.24 (C-6), 150.08 (C-3’’’’ & C-5’’’’), 147.65 (C-2), 143.95 (C-5), 136.54 (C-3’’), 135.57 (C-1’’), 134.21 (C-4’’’’), 131.40 (C-1’’’’), 130.77 (C- 2’’’’ & C-6’’’’), 126.69* (C-4’’ & C-5’’), 126.60 (C-2’’), 123.48 (C-6’’), 117.12 (C-3), 111.41 (C-4), 45.55* ( C-2’, C-3’, C-5' & C-6'), 36.21 (C- 8’’); EI-MS (m/z): 564 [M]⁺, 496 [C₅H₃O₂]⁺ 467 [C₂₀H1₅N₆O₆S]⁺, 385 [C1₆H9N₄O₆S]⁺, 318 [C₁₂H₆N₄O₅S]^•+ 246 [C₅H₃O₂]•⁺ 236 [C₈H₄N₄O⁵]⁺, 179 [C9H_uN₂O₂]⁺, 151 N₄, 118 [C₆H₂N₂O]⁺, 95 [C₅H₃O₂]⁺.

Biological Activities Assays

Acetylcholinesterase (AChE) Assay

The AChE inhibition activities were performed according to the reported method with slight modifications. Total volume of the reaction mixture was 100μL. It contained 60 μL Na2HPO4 buffer with concentration of 50 mM and pH 7.7. 10 μL test compound (0.5 mM well-1) was added, followed by the addition of 10 μL (0.005 unit well-1) enzyme. The contents were mixed and pre-read at 405 nm. Then contents were pre-incubated for 10 min at 37 °C. The reaction was initiated by the addition of 10 μL of 0.5 mM well-1 substrate (acetylthiocholine iodide), followed by the addition of 10μL DTNB (0.5mM well-1). After 15 min of incubation at 37 °C absorbance was measured at 405 nm using 96-well plate reader Synergy HT, Biotek, USA. All experiments were carried out with their respective controls in triplicate. Eserine (0.5mM well-1) was used as a positive control. The percent inhibition was calculated by the help of following equation IC50 values were calculated using EZ�Fit Enzyme kinetics software (Perrella Scientific Inc. Amherst, USA) [25].

Antibacterial and antifungal Assay

Disc diffusion method was used to find out the antimicrobial activity of the synthesized compounds. 100μL suspensions of tested microorganisms was spread on PDA medium for 106 spores/mL of fungi and on NA medium for 107 colony-forming units/mL of bacteria cells. The filter discs of 6mm diameter were saturated with compound solution and placed on the agar plates inoculated with the tested microorganisms. Filter discs without samples were employed as negative control. Rifamicin (30|ig/disk) and Fluconazole (30|ig/disk) were applied as positive reference for bacterial strains and fungal strains, respectively. Plates were placed 4 °C for 2 hours and then incubated at 37 °C for 18 hours for bacterial strains and at 28 °C for 24 hours for fungal strains. Antimicrobial activity was justified after comparison of diameter of growth inhibition zone measured in mm for organisms and the controls [26].

Hemolytic Activity

Hemolytic activity of the compound was studied by the reported method. 3 mL freshly obtained heparinized bovine blood was collected. Blood was centrifuged for 5 min at 1000 x g plasma was discarded and cells were washed three times with 5 mL of chilled (4 oC) sterile isotonic phosphate-buffer saline (PBS) at pH 7.4. Erythrocytes were maintained 108 cells per mL for each assay. Hundred μL of each compound was mixed with human (108 cells/ mL) separately. Samples were incubated for 35 min at 37 oC and agitated after 10 min. Immediately after incubation the samples were placed on ice for 5 min then centrifuged for 5 min at 1000 x g. Supernatant 100μL were taken from each tube and diluted 10 time with chilled (4 oC) PBS. Triton X-100 (0.1 % v/v) was taken as positive control and phosphate buffer saline (PBS) was taken as negative control and passed through the same process. The absorbance was noted at 576 nm using nQuant (Bioteck, USA). The % RBCs lysis for each sample was calculated [27, 28].

Results and Discussion

Chemistry

Table 1: Different substituent in scheme 1.

The presented study describes the synthesis of some novel tri-heterocyclic benzamides, 8a-g, following a facile strategy in multi-steps (Scheme 1 & Table 1). In first part, an electrophonic, {4-[3-(chloromethyl)benzoyl]-1-piperazinyl}(2-furyl)methadone (3) , was synthesized by the reaction of 2-Furoyl-1-piperazine (1) and 3-chloromethylbenzoyl chloride (2). The second part consisted a series of convergent steps, where, different carboxylic acids, 4a-g, were refluxed with ethanol and conc. sulfuric acid to form esters, 5a-g. These esters were further refluxed with N2H4.H2O in methanol solution to acquire acid respective hydrazides, 6a-g. These hydrazides were cyclized by refluxing with KOH, ethanol and CS2 into corresponding 1,3,4-oxadiazoles, 7a-g. In the final part of the synthesis, the electrophile, 3, was coupled with synthesized 1,3,4-oxadiazoles, 7a-g, in acetonitrile and potassium carbonate to acquire the targeted novel tri-heterocyclic molecules, 8a-g, in good yields. Structures of these novel compounds were confirmed by IR, 1H-NMR, ¹³C-NMR and EI-MS techniques. The structure of one of the compounds is discussed hereby in detail for the benefit of the readers. The molecular formula, C₂₅H₂₂N₄O₅S, of 8e was established through it EI-MS spectrum showing molecular ion peak at m/z 490 g/mol. The number of protons and in its 1H-NMR, and number of carbon resonances in its 13C-NMR spectrum also supported this assignment. The IR spectrum well supported the molecular functionalities by distinct absorption bands at 3075 (Ar C-H), 2889 (R C-H), 1654 (C=O), 1585 (Ar C=C), 1201 (C-O-C), 1109 (C-N-C) and 655 (C-S). In 1H-NMR spectrum, signals of methylbenzamide moiety appeared at 5 7.53 (br.s, 1H, H-2”), 7.46 (d, J = 6.1 Hz, 1H, H-6"), 7.40 (t, J = 7.6 Hz, 1H, H-5"), 7.33 (d, J = 7.4 Hz, 1H, H-4") and 4.43 (s, 2H, CH2-8”). The signals of protons for 4-hydroxyphenyl ring appeared at 7.71 (d, J = 8.3 Hz, 2H, H-2””, H-6””) and 6.86 (d, J = 8.4 Hz, 2H, H-3””, H-5””). Furan ring showed three peaks in aromatic region at 5 7.52 (br.s, 1H, H-5), 7.04 (d, J = 3.4 Hz, 1H, H-3) and 6.47 (dd, J = 1.3, 3.0 Hz, 1H, H-4). The eight protons of piperazine ring appeared at 5 3.82 (br.s, 4H, CH2-3’, CH2-5') and 3. (br.s, 4H, CH2-2’, CH2-6') (Figure 1a & Figure 1b). The structure was also thorough supported by its 13C-NMR spectrum (Figure 2a &Z Figure 2b). The distinct peak at m/z 194 in its EI-MS spectrum was related to 5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-thiol, the peak at m/z 119 was related to 4-hydroxyphenylcyanide moiety while the peak at m/z 95 to furoyl part of the molecule (Figure 3). So, on the basis of above cumulative evidences, the molecule 8e was named as {4-[3-({[5-(4-Hydroxyphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl} methyl)benzoyl]-1-piperazinyl} (2-furyl)methanone. Similarly, the structures of all other synthesized derivatives were characterized by aforesaid pattern.

Scheme 1: Outline for the synthesis of novel tri-heterocyclic benzamides. Reagents & Conditions: (I) Aq. Na₂CO₃ soln./pH 9-10/ stirring at RT for 4 hrs. (II) EtOH/H₂SO₄/refluxing for 3-4 hrs. (III) MeOH/N₂H₄ • H₂O/refluxing for 4-6 hrs. (IV) EtOH/CS₂/ KOH/refluxing for 3-6 hrs. (V) Acetonitrile/K2CO₃/refluxing for 0.5 hrs for activation of 7a-g (one in each reaction), followed by addition of 3 and finally refluxing for 4-5 hrs to obtain 8a-g.

Figure 1a: Aromatic region of 1H-NMR for 8e.

Figure 1b: Aliphatic region of 1H-NMR for 8e.

Figure 2a: Aromatic region of ¹³C-NMR for 8e.

Figure 2b: Aliphatic region of ¹³C-NMR for 8e.

Figure 3: Mass spectrum of 8e.

Biological activities

The novel tri-heterocyclic molecules, 8a-g, were screened for biological activities such as enzyme inhibition, hemolytic activity, biological and fungal activity to ascertain their possible therapeutic potential for the associated ailments.

AChE inhibitory potential

All the synthesized compounds 8a-g was screened against acetyl cholinesterase for enzyme inhibition potential. Among these synthesized compounds, the molecule 8b and 8g exhibited inhibitory potential of 87.36±0.19 and 52.85±0.15 relative to serine 91.27±1.17, a reference standard (Table 2).

Table 2: AChE inhibition of synthesized compounds, 8a-g

Antibacterial activity

To study the antibacterial activity of the synthesized molecules, 8a-g was screened for antibacterial activity against Gram-positive stain Bacillus subtilis and Gram-negative strain Escherichia coli. Rifamicin was used as reference standard in this study (Table 3). Compounds 8c and 8f showed good inhibitory potential against the bacterial strains used in this study, especially compound 31c with values of 12 μM and 15 μM against B. subtilis and E. coli respectively.

Antifungal activity

The result of antifungal activity was also shown in Table 3. For anti-fungal activity the synthesized molecules, 8a-g were screened against A. flavus. The compounds 8c and 8f exhibited good antifungal activity against fungal strain in addition to the antibacterial activity. Fluconazole was used as reference standard in this study (Table 3).

Table 3: Antibacterial and Antifungal activities (zone of inhibition, mm) of synthesized compounds, 8a-g.

Hemolytic activity

The results of hemolytic activity assay revealed that all tested compounds ranged below the positive control Triton-X-100. Highest hemolytic activity was shown by 8c (86.67 %) which was lower than the positive control Triton-X-100 (Table 4). Other compounds mostly showed low hemolytic activity. The lowest activity was shown by 8f (1.89 %) but higher than the negative controls PBS- 0.09.

Table 4: Hemolytic activity of synthesized compounds, 8a-g.

Structure-activity relationship

Among the synthesized compounds, only two compounds remained potent against the three microbial strains taken into account. The active compounds were 8c and 8f bearing 3-nitrophenyl and 2,4-dichlorophenyl groups, respectively. These compounds showed zone of inhibition as 12, 15 & 12 and 9, 11, & 10 mm against B. subtilis, E. coli & A. flavus, respectively, with reference of 22, 25 & 19 mm. The cytotoxicity of the synthesized molecules was also investigated through hemolytic activity analysis. The highest hemolytic activity was shown by 8c (86.67 %) having bearing 3- nitrophenyl group but it was lower than the positive control (Triton-X-100). The lowest activity in the series was exhibited by 8f (1.89 %) which was incorporating 2,4-dichlorophenyl moiety in its structure. Only two compounds, 8b and 8g, bearing 3-aminophenyl and 3,5-dinitrophenyl group, respectively, remained moderately low active against AChE enzyme.

Conclusion

The structures of the synthesized novel tri-heterocyclic molecules, 8a-g, were thoroughly corroborated by spectroscopic analysis. The newly synthesized compounds were screened for enzyme inhibition, antibacterial, antifungal and hemolytic activity. The data in the (Table 1) indicated that among the synthesized compound 8b exhibit good enzyme inhibition. Some of the compounds exhibited suitable antibacterial and antifungal potential against B. subtilis, E. coli and A. flavus strains. Particularly, 8c displayed the maximum inhibition. The cytotoxic results have also been processed to evaluate the cytotoxicity of the synthesized molecules and found a few of them toxic up to some extent and others with less toxicity. From the results of various biological activities it was concluded that these compounds would be of better use in drug development to combat bacterial infections and as antifungal agents in the future.

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