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Article

1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents

by
Michelyne Haroun
1,*,
Santosh S. Chobe
2,
Rajasekhar Reddy Alavala
3,*,
Savita M. Mathure
4,
Risy Namratha Jamullamudi
5,
Charushila K. Nerkar
6,
Vijay Kumar Gugulothu
7,
Christophe Tratrat
1,
Mohammed Monirul Islam
8,
Katharigatta N. Venugopala
1,9,
Mohammed Habeebuddin
10,
Mallikarjun Telsang
11,
Nagaraja Sreeharsha
1,12,* and
Md. Khalid Anwer
13
1
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Hofuf 31982, Al-Ahsa, Saudi Arabia
2
MGV’s L.V.H. Arts, Science and Commerce College, Panchavati, Nashik 422009, India
3
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India
4
MGV’s M. S. G. Arts, Science and Commerce College, Malegaon-Camp, Tal-Malegaon, Nashik 423203, India
5
Koneru Lakshmaiah Education Foundation, K L College of Pharmacy, Guntur 522502, India
6
MGV’s Arts, Science and Commerce College, Manmad 422009, India
7
Janagoan Institute of Pharmaceutical Sciences, Janagoan 506167, India
8
Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Hofuf 31982, Al-Ahsa, Saudi Arabia
9
Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban 4000, South Africa
10
Department of Biomedical Sciences, College of Medicine, King Faisal University, Al-Hofuf 31982, Al-Ahsa, Saudi Arabia
11
Department of Surgery, College of Medicine, King Faisal University, Al-Hofuf 31982, Al-Ahsa, Saudi Arabia
12
Department of Pharmaceutics, Vidya Siri College of Pharmacy, Off Sarjapura Road, Bangalore 560035, India
13
Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Alkharj 11942, Saudi Arabia
 
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*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(12), 3757; https://doi.org/10.3390/molecules27123757
Submission received: 9 May 2022 / Revised: 8 June 2022 / Accepted: 8 June 2022 / Published: 10 June 2022
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Considering the importance of benzothiazepine pharmacophore, an attempt was carried out to synthesize novel 1,5-benzothiazepine derivatives using polyethylene glycol-400 (PEG-400)-mediated pathways. Initially, different chalcones were synthesized and then subjected to a cyclization step with benzothiazepine in the presence of bleaching clay and PEG-400. PEG-400-mediated synthesis resulted in a yield of more than 95% in less than an hour of reaction time. Synthesized compounds 2a–2j were investigated for their in vitro cytotoxic activity. Moreover, the same compounds were subjected to systematic in silico screening for the identification of target proteins such as human adenosine kinase, glycogen synthase kinase-3β, and human mitogen-activated protein kinase 1. The compounds showed promising results in cytotoxicity assays; among the tested compounds, 2c showed the most potent cytotoxic activity in the liver cancer cell line Hep G-2, with an IC50 of 3.29 ± 0.15 µM, whereas the standard drug IC50 was 4.68 ± 0.17 µM. In the prostate cancer cell line DU-145, the compounds displayed IC50 ranges of 15.42 ± 0.16 to 41.34 ± 0.12 µM, while the standard drug had an IC50 of 21.96 ± 0.15 µM. In terms of structural insights, the halogenated phenyl substitution on the second position of benzothiazepine was found to significantly improve the biological activity. This characteristic feature is supported by the binding patterns on the selected target proteins in docking simulations. In this study, 1,5-benzothiazepines have been identified as potential anticancer agents which can be further exploited for the development of more potent derivatives.
Keywords: 1,5-benzothiazepines; PEG-400; molecular docking; cytotoxicity; anticancer 1,5-benzothiazepines; PEG-400; molecular docking; cytotoxicity; anticancer

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MDPI and ACS Style

Haroun, M.; Chobe, S.S.; Alavala, R.R.; Mathure, S.M.; Jamullamudi, R.N.; Nerkar, C.K.; Gugulothu, V.K.; Tratrat, C.; Islam, M.M.; Venugopala, K.N.; et al. 1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents. Molecules 2022, 27, 3757. https://doi.org/10.3390/molecules27123757

AMA Style

Haroun M, Chobe SS, Alavala RR, Mathure SM, Jamullamudi RN, Nerkar CK, Gugulothu VK, Tratrat C, Islam MM, Venugopala KN, et al. 1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents. Molecules. 2022; 27(12):3757. https://doi.org/10.3390/molecules27123757

Chicago/Turabian Style

Haroun, Michelyne, Santosh S. Chobe, Rajasekhar Reddy Alavala, Savita M. Mathure, Risy Namratha Jamullamudi, Charushila K. Nerkar, Vijay Kumar Gugulothu, Christophe Tratrat, Mohammed Monirul Islam, Katharigatta N. Venugopala, and et al. 2022. "1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents" Molecules 27, no. 12: 3757. https://doi.org/10.3390/molecules27123757

APA Style

Haroun, M., Chobe, S. S., Alavala, R. R., Mathure, S. M., Jamullamudi, R. N., Nerkar, C. K., Gugulothu, V. K., Tratrat, C., Islam, M. M., Venugopala, K. N., Habeebuddin, M., Telsang, M., Sreeharsha, N., & Anwer, M. K. (2022). 1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents. Molecules, 27(12), 3757. https://doi.org/10.3390/molecules27123757

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