Computational Screening, ADME Study, and Evaluation of Benzothiazole Derivatives as Potential Anticancer Agents.

Abstract

Introduction: Benzothiazole derivatives have garnered considerable interest in medicinal chemistry due to their diverse biological activities, including anticancer potential. The synthesis of 2-substituted benzothiazoles is traditionally achieved via two main approaches: (1) condensation of 2-aminothiophenols with aldehydes or carboxylic acid derivatives under highly acidic conditions, and (2) cyclization of thiobenzanilides. In this study, approximately 65 benzothiazole analogs were evaluated for anticancer potential using in silico tools and ADME profiling.

Materials and methods: ADME properties were predicted using SwissADME, while molecular docking studies were performed using Molegro Virtual Docker 6.0. Gefitinib and Erlotinib were used as reference drugs for both pharmacokinetic and in silico comparisons. Biological activity predictions were conducted using the PASS online web server.

Results: Docking scores for the analogs ranged from -134.60 to -114.36, with several compounds outperforming standard drugs Gefitinib (-122.87) and Erlotinib (-119.22). Compounds 12, 17, 27, 43, and 49 exhibited five hydrogen bond interactions, whereas compound 45 showed a maximum of six, exceeding the interactions observed for the standard drugs. Most compounds had molecular weights below 500 and favorable Log P values (e.g., compounds 4: 2.34, 5: 2.85, 7: 2.56, 10: 2.76, 17: 2.78, 19: 2.51, 26: 2.09, 30: 1.20, 40: 1.78, 45: 1.76, 56: 1.75), lower than the reference drugs (3.92, 3.20). Selected compounds also displayed improved topological polar surface area (TPSA) values (e.g., 5: 80.05 Ų, 11: 79.46 Ų, 13: 71.83 Ų, 15: 87.74 Ų, 23: 68.82 Ų, 32: 61.36 Ų, 36: 45.53 Ų, 52: 41.13 Ų) compared to standard drugs (68.74 Ų, 74.73 Ų). Targeting EGFR using PASS predictions, compounds 32, 33, 35, 39, 46, and 48 exhibited activities similar to Gefitinib and Erlotinib.

Discussion: Docking and ADME analyses indicated that several benzothiazole analogs outperformed standard drugs in binding affinity and pharmacokinetic profiles. EGFR, a transmembrane receptor tyrosine kinase, plays a central role in cell proliferation, survival, angiogenesis, and migration. Most compounds demonstrated good gastrointestinal absorption, suggesting favorable oral bioavailability according to Lipinski, Ghose, Veber, Egan, and Muegge rules. PASS predictions indicated potential anticancer activities, including inhibition of transcription factor STAT3, DNAdirected RNA polymerase, Mcl-1, proto-oncogene tyrosine-protein kinase Fgr, and EGFR, with potential antineoplastic effects across multiple cancer types, including solid tumors, lung, gastric, lymphoma, sarcoma, breast, and pancreatic cancers.

Conclusion: Compounds 12, 17, 27, 43, 45, and 49 demonstrated strong binding affinities and superior pharmacokinetic profiles compared to Gefitinib and Erlotinib. Overall, benzothiazole derivatives represent a promising scaffold for the design of EGFR inhibitors, potentially contributing to targeted anticancer therapy.