Synthesis of thiazole linked pyrimidine and chalcone derivatives: in-vitro anticancer studies and in-silico molecular docking simulations

Abstract

The synthesis of thiazole linked pyrimidine and chalcone derivatives 20a-j was achieved by the Claisen-condensation reaction between thiazole-aldehyde and different types of aryl ketones in the presence of piperidine in ethanol at reflux for 12 h time. These derivatives were tested for their cytotoxicity values against MCF-7, A2780, A549 and Colo-205 cell lines with Etoposide as standard drug by utilizing MTT reduction assay protocol. Among the synthesized derivatives, the derivative 20a with 3,4,5-trimethoxyaryl ring showed superior anticancer effect on all cell lines, with IC₅₀ values from MCF-7 = 0.05 ± 0.007 µM; A549 = 0.11 ± 0.047 µM; Colo-205 = 0.66 ± 0.062 µM and A2780 = 0.96. ± 0.075 µM. Molecular docking studies targeting human Topoisomerase IIβ revealed that several synthesized compounds, 20a, 20b, 20f, 20 g, and 20j exhibited notable binding affinities (− 5.9 to − 5.5 kcal/mol) in comparison to the standard drug Etoposide (− 6.5 kcal/mol). These candidates showed favourable interactions with critical active site residues such as GLN778, ASP479, ARG503, and MET782, which are crucial for stabilizing the topoisomerase–DNA complex. The interaction patterns suggest a potential mechanism for modulation at the protein-DNA interface. Among these, compound 20a exhibited a favourable binding and interaction profile, positioning it as a promising hit for the development of novel anticancer therapeutics.

Graphical abstract

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