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.

To shed light on the significance of indenyl-derived thiazole derivatives in the advancement of cancer medication and to contribute to therapeutic innovation, we present 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. A one-pot, multicomponent reaction between 5-aminoindane and phenyl isothiocyanate proceeds effectively under neat grinding reaction conditions to generate 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 the most active against MCF-7 breast cancer/A-549 lung cancer and non-cancerous normal VERO cells with average GI50 values 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 simulations showed that compound (8c) maintained 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 the existing method for the synthesis of the titled compounds with effective biological applications.