Generic placeholder image

Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis, Biological Evaluation, and Docking Analysis of Novel Tetrahydrobenzothiophene Derivatives

Author(s): Raghav Mishra*, Nitin Kumar and Neetu Sachan

Volume 19, Issue 6, 2022

Published on: 21 February, 2022

Page: [530 - 540] Pages: 11

DOI: 10.2174/1570180819666220117123958

Price: $65


Background: The role of retinoic acid receptor-related orphan receptors in cancer development has raised the interest to develop multi-functional agents.

Objective: The main purpose of this work was in silico design and synthesis of potential anticancer candidates with antioxidant effect.

Methods: The compounds were designed based on their docking studies with respect to the RORγt receptor. Using the Gewald protocol, a series of new tetrahydrobenzothiophene derivatives was synthesized. The physicochemical and spectroanalytical findings, including FTIR, 1H-NMR, 13C-NMR, and mass spectroscopic techniques, verified the molecular structures of the synthesized derivatives. The anticancer and antioxidant potential of the synthesized compounds was assessed in vitro. The compounds were tested by the National Cancer Institute, USA for anticancer action towards different cell lines representing nine cancerous conditions. The antioxidant activity of compounds was assessed in vitro using the DPPH free radical scavenging method.

Results: Docking analysis on RORγt receptors revealed that the test compounds have anticancer potential. Within the binding pocket of the chosen PDB ID (6q7a), RCA3 and RCA5 showed good docking scores in molecular docking studies, validating their capability of being used in rational drug design as lead compounds. Compounds showed diversified ratios of anticancer activity. RCA5 and RCA7 showed excellent antioxidant activity in reference to ascorbic acid with IC50 values of 18.71μg/mL and 20.88μg/mL.

Conclusion: Cytotoxicity results very well complemented the docking scores. Compounds RCA3 and RCA5 displayed higher anticancer activity in the subpanels of leukemia, breast cancer, and lung cancer. Compounds RCA5 and RCA7 displayed potent antioxidant action comparable to ascorbic acid, while other compounds presented mild to good antioxidant behavior.

Keywords: Tetrahydrobenzothiophene, gewald reaction, synthesis, structure activity relationships, anticancer activity, antioxidant activity, ROR.

Graphical Abstract
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[] [PMID: 30207593]
Kumar, V.; Abbas, A.K.; Fausto, N. Robbins & Cotran Pathologic Basis of Disease; Elsevier Health Sciences, 2009.
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[] [PMID: 25220842]
Varmus, H. The new era in cancer research. Science, 2006, 312(5777), 1162-1165.
[] [PMID: 16728627]
Archna; Pathania, S.; Chawla, P.A. Thiophene-based derivatives as anticancer agents: An overview on decade’s work. Bioorg. Chem., 2020, 101(104026), 104026.
[] [PMID: 32599369]
Singh, P.K.; Silakari, O. The current status of O-heterocycles: A synthetic and medicinal overview. ChemMedChem, 2018, 13(11), 1071-1087.
[] [PMID: 29603634]
Pathania, S.; Narang, R.K.; Rawal, R.K. Role of sulphur-fheterocycles in medicinal chemistry: An update. Eur. J. Med. Chem., 2019, 180, 486-508.
[] [PMID: 31330449]
de Jong, S.; Kooistra, A.J.; de Vries, E.G.; Mulder, N.H.; Zijlstra, J.G. Topoisomerase II as a target of VM-26 and 4′-(9-acridinylamino)methanesulfon-m-aniside in atypical multidrug resistant human small cell lung carcinoma cells. Cancer Res., 1993, 53(5), 1064-1071.
[PMID: 8382551]
Ashalatha, B.V.; Narayana, B.; Vijaya Raj, K.K.; Suchetha Kumari, N. Synthesis of some new bioactive 3-amino-2-mercapto-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives. Eur. J. Med. Chem., 2007, 42(5), 719-728.
[] [PMID: 17189665]
Shafeeque, S.; Mohan, S.; Manjunatha, K.S. Synthesis, analgesic and antiinflammatory activity of some 2-substituted amino-3-(N-p-Tolyl Carboxamido)-4,5-dimethyl thiophenes. Indian J. Heterocycl. Chem., 1999, 8(4), 297-300.
Mishra, R.; Tomer, I.; Kumar, S. Synthesis and antimicrobial evaluation of novel thiophene derivatives. Pharm. Sin., 2012, 3, 332-336.
Kotaiah, Y.; Harikrishna, N.; Nagaraju, K.; Venkata Rao, C. Synthesis and antioxidant activity of 1,3,4-oxadiazole tagged thieno[2,3-d]pyrimidine derivatives. Eur. J. Med. Chem., 2012, 58, 340-345.
[] [PMID: 23149297]
Malani, K.; Thakkar, S.S.; Thakur, M.C.; Ray, A.; Doshi, H. Synthesis, characterization and in silico designing of diethyl-3-methyl-5-(6-methyl-2-thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido) thiophene-2,4-dicarboxylate derivative as anti-proliferative and anti-microbial agents. Bioorg. Chem., 2016, 68, 265-274.
[] [PMID: 27616159]
Wang, S.Q.; Fang, L.; Liu, X.J.; Zhao, K. Design, synthesis, and hypnotic activity of pyrazolo[1,5-a]pyrimidine derivatives. Chin. Chem. Lett., 2004, 15(8), 885-888.
Ortiz, M.A.; Piedrafita, F.J.; Pfahl, M.; Maki, R. TOR: A new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. Mol. Endocrinol., 1995, 9(12), 1679-1691.
[] [PMID: 8614404]
Fan, J.; Lv, Z.; Yang, G.; Liao, T.T.; Xu, J.; Wu, F.; Huang, Q.; Guo, M.; Hu, G.; Zhou, M.; Duan, L.; Liu, S.; Jin, Y. Retinoic acid receptor-related orphan receptors: Critical roles in tumorigenesis. Front. Immunol., 2018, 9, 1187.
[] [PMID: 29904382]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991, 83(11), 757-766.
[] [PMID: 2041050]
Boyd, M.R.; Paull, K.D. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev. Res., 1995, 34(2), 91-109.
Boyd, M.R. Status of the NCI preclinical antitumor drug discovery screen. Princip. Prac. Oncol., 1989, 3, 1-12.
Gundogdu-Karaburun, N.; Karaburun, A.; Demirayak, S.; Kayagil, I.; Yurttas, L. Synthesis and anticancer activity of some 2-[3/4-(2-substituted phenyl-2-oxoethoxy)benzylidene]-6-substituted-2,3-dihydro-1h-inden-1-one derivatives. Lett. Drug Des. Discov., 2014, 11(5), 578-585.
Shimada, K.; Fujikawa, K.; Yahara, K.; Nakamura, T. Antioxidative properties of xanthan on the autoxidation of soybean oil in cyclodextrin emulsion. J. Agric. Food Chem., 1992, 40(6), 945-948.
Shah, R.; Verma, P.K. Synthesis of thiophene derivatives and their anti-microbial, antioxidant, anticorrosion and anticancer activity. BMC Chem., 2019, 13(1), 54.
[] [PMID: 31384802]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy