2D-Quantitative structure activity relationship (QSAR) modeling, docking studies, synthesis and in-vitro evaluation of 1,3,4-thiadiazole tethered coumarin derivatives as antiproliferative agents

Abstract

Cancer is one of the leading causes of deaths globally. Despite many anticancer agents in the market, cancer stood as a major health concern to humanity due to the problems like drug resistance, toxicities and economic burden etc., and these issues strongly impose the scientists for the development of novel anticancer agents. Hence, in the current investigation, we performed the 2D-QSAR (Quantitative Structure-Activity Relationship) analysis of a series of compounds reported with a potential antiproliferative activity using multiple regression analysis and designed compounds from the obtained QSAR model. The generated Multiple Linear Regression (MLR) equations were validated both internally and externally. The applicability domain has been done for the developed model. Based on the generated QSAR equations, a series of 2-amino-5-substituted-1,3,4-thiadiazole derivatives were designed and their antiproliferative activity was predicted using the QSAR equations. Further, molecular docking studies were carried out for the designed compounds using Autodock 4 against Epidermal Growth Factor Receptor (EGFR) kinase. The compounds with good binding affinity were synthesized and characterized by FT-IR, NMR and mass spectroscopy and evaluated for their antiproliferative activity against MCF-7 and PC3 cell lines considering the overexpression of EGFR kinase in breast and prostate cancers. The generated best model exhibited an r2 value of 0.93, q2LOO = 0.92, r2cv = 0.78. From the results, compound 3b and 3c exhibited good antiproliferative activity. The results of the study suggest that the synthesized active compound could serve as a lead for generating good biological agents against EGFR kinase.

Keywords

• QSAR
• Antiproliferative
• Thiadiazole
• Coumarin
• Docking
• Regression