In-Silico Molecular Docking, ADME Prediction and In-vivo Toxicity Study of 1,5-Benzothiazepine Derivatives as Potent Anticonvulsant Agent
DOI:
https://doi.org/10.37285/ijpsn-aktu.2022-25Abstract
Background: Epilepsy is broadly communal serious neurological conditions, affecting millions of individual worldwide. It’s mostly distributed and spread with the greater chance especially in infants and aged individuals. The derivatives of 1,5-benzothiazepine are of promising in discovery as they have found effective against various aspects. Thus, 1,5-benzothiazepines are highly medicinally significant compound that has made invented a no. of methods for synthesis and transformation.
Objective: In this present investigation, three novel compounds of 1,5-benzothiazepine were chosen for predicting in-silico molecular docking, ADME prediction, and acute oral toxicity studies.
Methods: All computational studies were performed using SwissDock web service. PDB id refers 3IP9, acquired from RCSB protein data bank and also performs in-silico ADME computational studies for determination of pharmacokinetic study. Further, preliminary safety profile was screened by oral acute toxicity as per OECD guidelines for most active compounds.
Results: We found that all the novel derivatives exhibited binding docking score in the range of 0-10 kcal/mol and inhibition constant 1-90 µM. The most active derivatives A3, B5 and C5 were almost same docking scores phenytoin as a standard drug. As per the Swiss ADME prediction analysis of 1, 5-benzothiazepine as potent pharmacophore follow Lipinski’s rule and showed satisfactory results. Further, preliminary safety profile was screened by oral acute toxicity studies for the most active compounds A3, B5 and C5, result suggest that these three compounds are safe and non-toxic in nature.
Conclusion: This study suggests that the 1,5-benzothiazepine heterocyclic nucleus is a potent pharmacophore molecule, further changes and improvement in domain of anticonvulsant drug development.
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Keywords:
Anticonvulsant, Docking, Drug Design, Lipinski’s rule, PhenytoinPublished
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Sameem, S.; Kumar, N.; Pathak, D. Synthesis and anticonvulsant activity of some newer semicarbazone derivatives. Int. J. Pharm. Sci. Drug Res., 2012, 4(3), 195-198.
Smita, P.; Rahul, K.; Dattatray, N. In-silico design of potential 1,5-benzothiazepine derivatives as an anti- convulsant agent by molecular docking studies. Int. J. Cli. Biomed. Res., 2019, 5(3), 29-36.
Kaur, R.; Singh, K.; Singh, R. 1, 5-Benzothiazepine: bioactivity and targets. Chem. Biol. Lett. , 2016, 3(1), 18-31.
Garg, N. Synthesis and evaluation of some new substituted benzothiazepine and benzoxazepine derivatives as anticonvulsant agents. Eur. J. Med. Chem., 2010, 45, 1529–1535.
Pandeya, S.N.; Kumar, D.; Verma, P.K. Newer applications of 1,5-benzothiazepines & their anticonvulsant activity. Der. Pharma. Chem., 2012, 4(5), 1853-1859.
Yaswanth, M.; Deepa, M.; Pramod, N.; Somashekar, B.; In-Silico design, synthesis, characterization and biological evaluation of novel 2-azetidinone derivatives for anti-Leukemic activity. J. PeerScientist, 2020, 2(1), 1-12.
Ali, R.; Siddiqui, N. Preliminary anticonvulsant and toxicity screening of substituted benzylidenehydrazinyl-N-(6-substituted benzo[d]thiazol-2-yl)propanamides. Sci. World J., 2014, 1-10.
Kurokawa, J.; Adachi-akahane, S.; Nagao, T. 1,5-Benzothiazepine binding domain is located on the extracellular side of the cardiac L-type calcium channel. Mol. Pharmacol., 1997, 51, 262–268.
Harshitha, T.; Kumar, T.V.; Vineetha, T. In silico characterization, molecular docking, and in vitro evaluation of triazole derivatives as potential anticancer agents. Asian. J. Pharm. Clin. Res., 2021, 14(2), 22-28.
Frimayanti, N.; Yaeghoobi, M.; Namavar, H.; Ikhtiarudin, I.; Afzali, M. In silico studies and biological evaluation of chalcone-based 1,5-benzothiazepines as new potential H1N1 neuraminidase inhibitors. J. Appl. Pharm. Sci., 2020, 10(10), 86-94.
Kumar, N.; Pathak, D. Docking, Synthesis and anticancer activity of some newer carbazole derivatives. Int. J. Pharm. Chem., 2016, 6(1), 51-59.
Kumar, N.; Pathak, D. Design, Synthesis and anticancer activity of 9-substituted carbazole derivatives. Int. J. Pharm. Chem. Res., 2016, 7(8), 3291-3298.
Kumar, N.; Pathak, D. Design, Synthesis and evaluation of novel 9-substituted carbazole derivatives as potential anticancer agents. Lett. Drug Des. Discov., 2015, 12(9), 760-765.
Bhrigu, B.; Siddiqui, N.; Pathak, D.; Alam, Md. S. Anticonvulsant evaluation of some newer benzimidazole derivatives: design and synthesis. Acta Pol. Pharm., 2012, 69, 53-62.
Sharma, C.S.; Mishra, S.S.; Singh, H.P.; Kumar, N. In silico ADME and toxicity study of some selected antineoplastic drugs. Int. J. Pharm. Sci. Drug Res., 2016, 8(1), 65-67.
Dixit, A.; Pathak, D.; Sharma, G.K. Synthesis, antibacterial and antioxidant activity of novel 12-(N-arylmethaniminyl)indolo[1,2-c]quinazolines. J. Res. Pharm., 2019, 23(3), 584-595.
Dixit, A.; Pathak, D.; Sharma, G.K. Synthesis, antibacterial and free radical scavenging activity of some newer N-((10-nitro-1H-indolo[1,2-c]quinazolin-12-yl)methylene)benzenamines. Eur. Pharm, J., 2019, 67(1), 7-16.
Dixit, A.; Pathak, D.; Sharma, G.K. A review on docking studies of indole moiety as potent inhibitor of tubulin polymerization. Eur. Chem. Bull., 2016, 5(11), (2016): 465-469.
Adeeb, Al Sheikh A.; Khan, D.; Naqvi, A.; Faleh Al-Blewi, F.; Rezki, N.; Reda Aouad, M.; Hagar, M. Design, synthesis, molecular modeling, anticancer studies, and density functional theory calculations of 4(1,2,4-triazol-3-ylsulfanyl- methyl)-1,2,3-triazole derivatives. ACS Omega., 2021, 6, 301−316.
Ansari, F.L.; Iftikhar, F.; Iulhaq, B.; Mirza, M.; Baseer, U.R. Solid phase synthesis and biological evaluation of parallel library of 2,3-dihydro-1,5-benzothiazepene. Bioorg. Med. Chem., 2008, 16, 7691-7697.
Shailee, V.; Tiwari, J.A.; Seijas, M.P.V.T.; Aniket, P.; Sarkate, K.S.; Karnik; Anna P.G. N. Facile synthesis of novel coumarin derivatives, antimicrobial analysis, enzyme assay, docking study, ADMET prediction and toxicity study. Molecules, 2017, 22, 1172-1190.
Livani, Z.L.; Safakish, M.; Hajimahdi, Z.; Soleymani, S.; Zabihollabhi, R.; Aghasadeghi, M.R.; Alipour, E.; Zarghi, A. Design, synthesis, molecular modeling, In-Silico ADME studies and anti-HIV-1 assay of new diazocoumarin derivatives. Ira. J. Pharm. Res., 2018, 17(2), 65-77.
Chaudhri, V.K.; Pathak, D.; Hussain, Z. Synthesis, preliminary anticonvulsant and toxicity screening of substituted 3-(dimethyl/ diethylamino)-{1-[4-methyl-2-substitutedphenyl-2,5-dihydro-1,5-benzothiazepin-3-yl]}propan-1-one. Int. J. Health Sci., 2022, 6(S5), 6752-6767.
Chaudhri, V.K.; Pathak, D.; Hussain, Z. Synthesis, preliminary anticonvulsant and toxicity screening of substituted {1-[4-methyl-2-substitutedphenyl-2,5-dihydro-1,5-benzothiazepin-3-yl]-ethylidene}-hydrazine. J. Appl. Pharm. Sci., 2021, 11, 16-23.
Gawai, A. A.; S. Das, S.; Nemade, M. Synthesis, preliminary pharmacological and acute toxicity studies of a new series of 7-(2-(benzo[d] thiazol-2-ylamino)ethoxy)-4-methyl-2H-chromen-2-one derivatives with atypical antipsychotic activity. Indian J. Pharm. Sci., 2019, 81(2), 241-248.
Cornel, C.; Aurelia, N.C.;, Manuella, M.; Simona, N.; Cristina, E.Z.; Diana, C.N. Pharmacological evaluation of acute and subacute toxicity and antidepressant effect after acute administration of novel N-substituted benzamides. Farm., 2010, 58(1), 21-28.
OECD, Test No. 420: Acute oral toxicity-fixed dose procedure. OECD guidelines for the testing of chemicals organization for economic cooperation and development. paris, France, 2001.
Pahari, N.; Saha, D.; Jain, V.K.; Jain, B.; Mridha, D. Evaluation of acute and subacute oral toxicity induced by ethanolic extract of marsdenia tenacissima leaves in experimental rats. Int. J. Pharm. Sci. Res., 2010, 9(2010), 399-408.
Porwal, M.; Khan, N.A.; Maheshwari, K.K. Evaluation of acute and subacute oral toxicity induced by ethanolic extract of marsdenia tenacissima leaves in experimental rats. Sci. Pharm., 2017, 85, 29-39
Mulukuri, N.V.L.S.; Dinesh, B.M.; Jha, D.K.; Prabhakar, T. Molecular docking and toxicity studies of series of compounds from diaryl urea hits & spiro piperidine indolinyl series as potential P2y1 receptor antagonists. Int. J. Pharm. Sci. Res., 2020, 11(4), 1934-1940.
