Rational design, synthesis, and molecular modelling insights of dual DNA binders/DHFR inhibitors bearing arylidene-hydrazinyl-1,3-thiazole scaffold with apoptotic and anti-migratory potential in breast MCF-7 cancer cells

In light of searching for new breast cancer therapies, DNA-targeted small molecules were rationally designed to simultaneously bind DNA and inhibit human dihydrofolate reductase (<i>h</i>DHFR). Fourteen new arylidene-hydrazinyl-1,3-thiazoles (<b>5–18</b>) were synthesised and their dual DNA groove binding potential and <i>in vitro h</i>DHFR inhibition were performed. Two compounds, <b>5</b> and <b>11</b>, proved their dual efficacy. Molecular docking and molecular dynamics simulations were performed for those active derivatives to explore their mode of binding and stability of interactions inside DHFR active site. Anti-breast cancer activity was assessed for <b>5</b> and <b>11</b> on MCF-7 cells using <b>MTX</b> as reference. IC₅₀ measurements revealed that both compounds were more potent and selective than <b>MTX</b>. Cytotoxicity was examined against normal skin fibroblasts to examine safety and selectivity Moreover, mechanistic studies including apoptosis induction and wound healing were performed. Further <i>in silico</i> ADMET assessment was conducted to determine their eligibility as drug leads suitable for future optimisation and development.