BN Sinha - Academia.edu (original) (raw)
Papers by BN Sinha
Letters in Drug Design & Discovery, 2016
A series of nineteen 2-aryl-4H-chromen-4-one derivatives 2a-2s were synthesized and evaluated for... more A series of nineteen 2-aryl-4H-chromen-4-one derivatives 2a-2s were synthesized and evaluated for their antiviral activity against Chikungunya virus (LR2006_OPY1) in Vero cell culture by CPE reduction assay. Three compounds 2a, 2b and 2g, were found to be active at concentration of (IC 50) 0.44 M, 0.45 M and 2.02 M, respectively. Compounds having heterocyclic ring 2a and 2b at the 2 nd position of the chromenone were found to be potent inhibitor of ChikV. Cytotoxicity studies were performed using Vero cell culture, compounds 2a and 2b exhibited SI of >100. Molecular docking simulation has been carried out to understand the possible mechanism of action.
The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves... more The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves of Capparis zeylanica Linn on experimental animal models. The methanol extract of Capparis zeylanica Linn. leaves was investigated for anti-ulcer activity against aspirin plus pylorus ligation induced gastric ulcer in rats. HCl-Ethanol induced ulcer in mice and indomethacin induced ulcer in rats at 200 mg/kg body weight p.o. A significant (p<0.01, p<0.001) anti-ulcer activity was observed in all the models. Pylorus ligation showed significant (p<0.01) reduction in gastric volume, free acidity and ulcer index as compared to control. It also showed 88.5% ulcer inhibition in HClethanol induced ulcer and 83.78% inhibition in indomethacin induced ulcer.
A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4−13, were s... more A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4−13, were synthesized and tested for their human MAO inhibitory activity. All the compounds were found to be selective and reversible toward hMAO-A except 4, a selective inhibitor of hMAO-B and 12, a nonselective inhibitor. Compound 7 was found to be a potent inhibitor of hMAO-A with K i = 0.06 ± 0.003 μM and was having selectivity index of (SI = 1.02 × 10 −5). It was found to be better than standard drug, Moclobemide (hMAO-A with K i = 0.11 ± 0.01 μM) with selectivity index of SI = 0.049. Molecular docking simulation was carried out to understand the crucial interactions responsible for selectivity and potency.
![Research paper thumbnail of Pyrazoline-based Mycobactin Analogues as Dual Inhibitors of MAO/Cholinesterase [MAO ve Kolinesteraz Dual İnhibitörü Pirazolin-Bazlı Mikobaktin Analogları] Research Article [Araştırma Makalesi]](https://attachments.academia-assets.com/83546524/thumbnails/1.jpg)
](Introduction: We earlier reported on anti-mycobacterial and monoamine oxida-se (MAO) inhibitory a... more Introduction: We earlier reported on anti-mycobacterial and monoamine oxida-se (MAO) inhibitory activity of 3, 5-diaryl-2-pyrazoline 1-carbothioamides with structural similarities to Mycobactin. The same thirty two compounds have been evaluated for Acetylcholinesterase (AChE) inhibitory activity in a search for dual
The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves... more The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves of Capparis zeylanica Linn on experimental animal models. The methanol extract of Capparis zeylanica Linn. leaves was investi-gated for anti-ulcer activity against aspirin plus pylorus ligation induced gastric ulcer in rats. HCl-Ethanol induced ulcer in mice and indomethacin induced ulcer in rats at 200 mg/kg body weight p.o. A significant (p<0.01, p<0.001) anti-ulcer activity was observed in all the models. Pylorus ligation showed significant (p<0.01) reduction in gastric volume, free acidity and ulcer index as compared to control. It also showed 88.5 % ulcer inhibition in HCl-ethanol induced ulcer and 83.78 % inhibition in indomethacin induced ulcer.
International Journal Bioautomation, 2020
Natural Product Research, 2022
Mini-Reviews in Medicinal Chemistry
: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China h... more : The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.
JOURNAL OF PHARMACEUTICAL CHEMISTRY
Ribonucleotide reductase(RNR) is a metalloenzyme that catalyses the rate limiting step in DNA syn... more Ribonucleotide reductase(RNR) is a metalloenzyme that catalyses the rate limiting step in DNA synthesis and repair. It causes the reduction of ribonucleotide to 2’-deoxyribonuclotides which are used as precursors for DNA synthesis, thus offering a good target for inhibition of cell synthesis. Experimental results have been proven that RNR inhibitors can be used as antiviral, anticancer or antibacterial agents. Here we report the synthesis of a novel class of diazeno-thiazole derivatives as potent RNR inhibitors. A series of forty molecules were synthesized and evaluated for their RNR inhibitory properties. All compounds were found to be good inhibitors of the RNR. Compound 3iwas found to be most active showing an IC50 value of 0.8 µm. The established SAR study indicated the presence of a polar bridge with an adjacent flexible aromatic ringprerequisite for RNR inhibitory activity. Moreover, compounds having an additional 4-chloro phenyl ring were found to be most potent.
European Journal of Pharmaceutical Sciences
European Journal of Pharmaceutical Sciences
European journal of medicinal chemistry, Jan 21, 2017
CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung c... more CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid 'O' atom with 'N' atom led to the prediction that a 'quinazoline' scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free fro...
Org. Biomol. Chem., 2016
Herein, we report the discovery of ‘biphenyl ureas’ as selective CYP1B1 inhibitors.
Journal of Natural Sciences Research, 2012
ABSTRACT Chikungunya virus (CHICKV) is an arboviruses belonging to family Tagoviridae and is tran... more ABSTRACT Chikungunya virus (CHICKV) is an arboviruses belonging to family Tagoviridae and is transmitted to human through by mosquito (Aedes aegypti and Aedes albopictus) bite. A large outbreak of chikungunya has been reported in India between 2006 and 2007, along with several other countries from South-East Asia and for the first time in Europe. It was for the first time that the CHICKV outbreak has been reported with mortality from Reunion Island and increased mortality from Asian countries. CHICKV affects all age groups, and currently there are no specific drugs or vaccine to cure the disease. The need of antiviral agents for the treatment of CHICKV infection and the success of virtual screening against many therapeutically valuable targets led us to carry out the structure based drug design against Chikungunya nSP2 protease (PDB: 3TRK). Highthroughput virtual screening of publicly available databases, ZINC12 and BindingDB, has been carried out using the Openeye tools and Schrodinger LLC software packages. Openeye Filter program has been used to filter the database and the filtered outputs were docked using HTVS protocol implemented in GLIDE package of Schrodinger LLC. The top HITS were further used for enriching the similar molecules from the database through vROCS; a shape based screening protocol implemented in Openeye. The approach adopted has provided different scaffolds as HITS against CHICKV protease. Three scaffolds: Indole, Pyrazole and Sulphone derivatives were selected based on the docking score and synthetic feasibility. Derivatives of Pyrazole were synthesized and submitted for antiviral screening against CHICKV.
Proceedings of The 19th International Electronic Conference on Synthetic Organic Chemistry, 2015
The sensation of pain is initiated in peripheral pain receptors (nociceptors) and its purpose is ... more The sensation of pain is initiated in peripheral pain receptors (nociceptors) and its purpose is to draw attention to tissue damage. In order to test analgesic activity, it is obviously necessary to induce pain in the subject and then modify the response to, or perception of, this pain. Analgesic studies of the methanol (90% v/v) extract (MELP) of Litsea polyantha Juss. bark (Yield: 11.79% w/w) was carried out using healthy adult Swiss albino mice of either sex weighing between 20 to 25 g respectively. The experiment protocols were approved by the Institutional Animal Ethical Committee (621/02/ac/CPCSEA) prior to the conduct of the animal experiments. The animals were divided into 6 groups (n=6). Group I and II were used as control, received 10% v/v propylene glycol (PG) and distilled water (DW) at the dose of 10 ml/kg b.w. Group III, IV & V were treated with MELP (50, 75 and 100 mg/kg b.w., i.p.), respectively; Group VI received Morphine sulphate (10 mg/kg b.w., s.c.) an opioid analgesic as standard drug. A reduction in the tail withdrawal as compared to the control group was considered as evidence for the presence of analgesia. Tail flick latency was measured 30 min after the drug administration and Pain Inhibition Percentage (PIP) was calculated. MELP given by intraperitoneal route in mice showed significant and dose-dependent central analgesic activity (P<0.001) at all dose levels. MELP showed 22.2%-60.4% increase in PIP in tail flick test and 21.2%-67.8% increase in PIP in tail immersion method.
Journal of Pharmaceutical and Biomedical Analysis, 2015
Sofosbuvir is a direct acting antiviral medication used to treat Hepatitis C viral infection. The... more Sofosbuvir is a direct acting antiviral medication used to treat Hepatitis C viral infection. The present study focuses on the degradation behavior of the drug under various stress conditions (hydrolysis, oxidative, thermal and photolytic) as per International Conference on Harmonization (ICH Q1A (R2)) guidelines. A high performance liquid chromatographic system (HPLC) was used to develop a selective, precise and accurate method for separating all the degradation products. The separation was achieved on a Sunfire™ C18 (150mm×4.6mm×5μm) stationary phase with a mobile phase of 10mM ammonium acetate (pH 5.0) buffer and acetonitrile in gradient elution mode. A quadrupole-time of flight mass analyzer equipped with an electrospray ionization technique was used to propose the structural information based on the MS/MS and accurate mass measurements. Seven degradation products were identified and characterised by LC-ESI-QTOF-MS/MS. In silico toxicity of the drug and its degradation products was determined using TOPKAT and DEREK toxicity prediction softwares. The proposed method was validated as per the ICH Q2 guidelines.
Archiv der Pharmazie, Jan 23, 2015
Ferulic acid has structural similarity with curcumin which is being reported for its monoamine ox... more Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a bet...
Letters in Drug Design & Discovery, 2016
A series of nineteen 2-aryl-4H-chromen-4-one derivatives 2a-2s were synthesized and evaluated for... more A series of nineteen 2-aryl-4H-chromen-4-one derivatives 2a-2s were synthesized and evaluated for their antiviral activity against Chikungunya virus (LR2006_OPY1) in Vero cell culture by CPE reduction assay. Three compounds 2a, 2b and 2g, were found to be active at concentration of (IC 50) 0.44 M, 0.45 M and 2.02 M, respectively. Compounds having heterocyclic ring 2a and 2b at the 2 nd position of the chromenone were found to be potent inhibitor of ChikV. Cytotoxicity studies were performed using Vero cell culture, compounds 2a and 2b exhibited SI of &gt;100. Molecular docking simulation has been carried out to understand the possible mechanism of action.
The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves... more The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves of Capparis zeylanica Linn on experimental animal models. The methanol extract of Capparis zeylanica Linn. leaves was investigated for anti-ulcer activity against aspirin plus pylorus ligation induced gastric ulcer in rats. HCl-Ethanol induced ulcer in mice and indomethacin induced ulcer in rats at 200 mg/kg body weight p.o. A significant (p<0.01, p<0.001) anti-ulcer activity was observed in all the models. Pylorus ligation showed significant (p<0.01) reduction in gastric volume, free acidity and ulcer index as compared to control. It also showed 88.5% ulcer inhibition in HClethanol induced ulcer and 83.78% inhibition in indomethacin induced ulcer.
A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4−13, were s... more A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4−13, were synthesized and tested for their human MAO inhibitory activity. All the compounds were found to be selective and reversible toward hMAO-A except 4, a selective inhibitor of hMAO-B and 12, a nonselective inhibitor. Compound 7 was found to be a potent inhibitor of hMAO-A with K i = 0.06 ± 0.003 μM and was having selectivity index of (SI = 1.02 × 10 −5). It was found to be better than standard drug, Moclobemide (hMAO-A with K i = 0.11 ± 0.01 μM) with selectivity index of SI = 0.049. Molecular docking simulation was carried out to understand the crucial interactions responsible for selectivity and potency.
Introduction: We earlier reported on anti-mycobacterial and monoamine oxida-se (MAO) inhibitory a... more Introduction: We earlier reported on anti-mycobacterial and monoamine oxida-se (MAO) inhibitory activity of 3, 5-diaryl-2-pyrazoline 1-carbothioamides with structural similarities to Mycobactin. The same thirty two compounds have been evaluated for Acetylcholinesterase (AChE) inhibitory activity in a search for dual
The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves... more The aim of the study was to study the anti-ulcer activity of the methanolic extract of the leaves of Capparis zeylanica Linn on experimental animal models. The methanol extract of Capparis zeylanica Linn. leaves was investi-gated for anti-ulcer activity against aspirin plus pylorus ligation induced gastric ulcer in rats. HCl-Ethanol induced ulcer in mice and indomethacin induced ulcer in rats at 200 mg/kg body weight p.o. A significant (p<0.01, p<0.001) anti-ulcer activity was observed in all the models. Pylorus ligation showed significant (p<0.01) reduction in gastric volume, free acidity and ulcer index as compared to control. It also showed 88.5 % ulcer inhibition in HCl-ethanol induced ulcer and 83.78 % inhibition in indomethacin induced ulcer.
International Journal Bioautomation, 2020
Natural Product Research, 2022
Mini-Reviews in Medicinal Chemistry
: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China h... more : The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.
JOURNAL OF PHARMACEUTICAL CHEMISTRY
Ribonucleotide reductase(RNR) is a metalloenzyme that catalyses the rate limiting step in DNA syn... more Ribonucleotide reductase(RNR) is a metalloenzyme that catalyses the rate limiting step in DNA synthesis and repair. It causes the reduction of ribonucleotide to 2’-deoxyribonuclotides which are used as precursors for DNA synthesis, thus offering a good target for inhibition of cell synthesis. Experimental results have been proven that RNR inhibitors can be used as antiviral, anticancer or antibacterial agents. Here we report the synthesis of a novel class of diazeno-thiazole derivatives as potent RNR inhibitors. A series of forty molecules were synthesized and evaluated for their RNR inhibitory properties. All compounds were found to be good inhibitors of the RNR. Compound 3iwas found to be most active showing an IC50 value of 0.8 µm. The established SAR study indicated the presence of a polar bridge with an adjacent flexible aromatic ringprerequisite for RNR inhibitory activity. Moreover, compounds having an additional 4-chloro phenyl ring were found to be most potent.
European Journal of Pharmaceutical Sciences
European Journal of Pharmaceutical Sciences
European journal of medicinal chemistry, Jan 21, 2017
CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung c... more CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid 'O' atom with 'N' atom led to the prediction that a 'quinazoline' scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free fro...
Org. Biomol. Chem., 2016
Herein, we report the discovery of ‘biphenyl ureas’ as selective CYP1B1 inhibitors.
Journal of Natural Sciences Research, 2012
ABSTRACT Chikungunya virus (CHICKV) is an arboviruses belonging to family Tagoviridae and is tran... more ABSTRACT Chikungunya virus (CHICKV) is an arboviruses belonging to family Tagoviridae and is transmitted to human through by mosquito (Aedes aegypti and Aedes albopictus) bite. A large outbreak of chikungunya has been reported in India between 2006 and 2007, along with several other countries from South-East Asia and for the first time in Europe. It was for the first time that the CHICKV outbreak has been reported with mortality from Reunion Island and increased mortality from Asian countries. CHICKV affects all age groups, and currently there are no specific drugs or vaccine to cure the disease. The need of antiviral agents for the treatment of CHICKV infection and the success of virtual screening against many therapeutically valuable targets led us to carry out the structure based drug design against Chikungunya nSP2 protease (PDB: 3TRK). Highthroughput virtual screening of publicly available databases, ZINC12 and BindingDB, has been carried out using the Openeye tools and Schrodinger LLC software packages. Openeye Filter program has been used to filter the database and the filtered outputs were docked using HTVS protocol implemented in GLIDE package of Schrodinger LLC. The top HITS were further used for enriching the similar molecules from the database through vROCS; a shape based screening protocol implemented in Openeye. The approach adopted has provided different scaffolds as HITS against CHICKV protease. Three scaffolds: Indole, Pyrazole and Sulphone derivatives were selected based on the docking score and synthetic feasibility. Derivatives of Pyrazole were synthesized and submitted for antiviral screening against CHICKV.
Proceedings of The 19th International Electronic Conference on Synthetic Organic Chemistry, 2015
The sensation of pain is initiated in peripheral pain receptors (nociceptors) and its purpose is ... more The sensation of pain is initiated in peripheral pain receptors (nociceptors) and its purpose is to draw attention to tissue damage. In order to test analgesic activity, it is obviously necessary to induce pain in the subject and then modify the response to, or perception of, this pain. Analgesic studies of the methanol (90% v/v) extract (MELP) of Litsea polyantha Juss. bark (Yield: 11.79% w/w) was carried out using healthy adult Swiss albino mice of either sex weighing between 20 to 25 g respectively. The experiment protocols were approved by the Institutional Animal Ethical Committee (621/02/ac/CPCSEA) prior to the conduct of the animal experiments. The animals were divided into 6 groups (n=6). Group I and II were used as control, received 10% v/v propylene glycol (PG) and distilled water (DW) at the dose of 10 ml/kg b.w. Group III, IV & V were treated with MELP (50, 75 and 100 mg/kg b.w., i.p.), respectively; Group VI received Morphine sulphate (10 mg/kg b.w., s.c.) an opioid analgesic as standard drug. A reduction in the tail withdrawal as compared to the control group was considered as evidence for the presence of analgesia. Tail flick latency was measured 30 min after the drug administration and Pain Inhibition Percentage (PIP) was calculated. MELP given by intraperitoneal route in mice showed significant and dose-dependent central analgesic activity (P<0.001) at all dose levels. MELP showed 22.2%-60.4% increase in PIP in tail flick test and 21.2%-67.8% increase in PIP in tail immersion method.
Journal of Pharmaceutical and Biomedical Analysis, 2015
Sofosbuvir is a direct acting antiviral medication used to treat Hepatitis C viral infection. The... more Sofosbuvir is a direct acting antiviral medication used to treat Hepatitis C viral infection. The present study focuses on the degradation behavior of the drug under various stress conditions (hydrolysis, oxidative, thermal and photolytic) as per International Conference on Harmonization (ICH Q1A (R2)) guidelines. A high performance liquid chromatographic system (HPLC) was used to develop a selective, precise and accurate method for separating all the degradation products. The separation was achieved on a Sunfire™ C18 (150mm×4.6mm×5μm) stationary phase with a mobile phase of 10mM ammonium acetate (pH 5.0) buffer and acetonitrile in gradient elution mode. A quadrupole-time of flight mass analyzer equipped with an electrospray ionization technique was used to propose the structural information based on the MS/MS and accurate mass measurements. Seven degradation products were identified and characterised by LC-ESI-QTOF-MS/MS. In silico toxicity of the drug and its degradation products was determined using TOPKAT and DEREK toxicity prediction softwares. The proposed method was validated as per the ICH Q2 guidelines.
Archiv der Pharmazie, Jan 23, 2015
Ferulic acid has structural similarity with curcumin which is being reported for its monoamine ox... more Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a bet...