Solvent and Catalyst-Free Mechanochemical Synthesis of Indenyl-Derived Thiazolone imine, Thiazolidin-4-one and Thiazolidin-4-ol Hybrids: Anticancer Evaluation and Molecular Modeling Studies

Abstract

To shed light on the significance of indenyl-derived thiazole derivatives in the advancement of cancer medication and to contribute to therapeutic innovation, we wish to disclose a facile, effective and sustainable protocol for the synthesis of novel indenyl-thiazol-2-imine, indenyl-thiazolidin-4-one and indenyl-thiazolidin-4-ol derivatives. One-pot, multicomponent reaction between 5-aminoindane, phenyl isothiocyanates proceed effectively under neat, grinding reaction condition generates thiocarbamide in-situ. This formed intermediate upon treatment with 2-bromoacetophenone, ethyl bromoacetate and 3-bromo-1,1,1-trifluoropropan-2-one affords (E)-N-(2,3-dihydro-1H-inden-5-yl)-3,4-diphenylthiazol-2(3H)-imine, (E)-2-((2,3-dihydro-1H-inden-5-yl)imino)-3-phenylthiazolidin-4-one and (E)-2-((2,3-dihydro-1H-inden-5-yl)imino)-3-phenyl-4-(trifluoromethyl)thiazolidin-4-ol respectively. Some of the synthesized compounds were evaluated for their in-vitro anticancer activities, and surprisingly the compound (E)-2-((2,3-dihydro-1H-inden-5-yl)imino)-3-(4-nitrophenyl)-4-(trifluoromethyl)- thiazolidin-4-ol (8c) was found to be most active against cancerous MCF-7 breast/A-549 lung cancer and non-cancerous normal VERO cell with average GI50 value of 0.1 μM and 0.9 μM respectively with reference to adriamycin. Molecular docking studies revealed that compound (8c) exhibits a favorable binding mode, supporting its potential as an EGFR inhibitor. Consistently, molecular dynamics showed compound (8c) maintains consistent ATP-pocket interactions without abnormal flexibility, further underscoring its promise as a potent EGFR targeting agent. In a nutshell, the proposed procedure offers an alternative way to existing method for synthesis of the titled compounds with effective biological applications.