Design, synthesis, and computational validation of novel benzothiazole derivatives as dual anticancer-antioxidant...

A novel series of benzothiazole-based thiosemicarbazides (5a-5d) and Schiff bases (6a-6r) were synthesized, characterized, and evaluated for their in vitro dual anticancer and antioxidant activities, representing benzothiazole derivatives designed to target VEGFR-2 with this dual functionality. Antiproliferative activity shown by 5b and 6b (IC₅₀ = 4.26 and 18.05 μM, respectively) against A-498 cell lines, while 5b and 6g showed IC₅₀ 10.78, 8.33 μM, respectively against HepG2. Following a two-step filtration process based on antiproliferative potency (IC₅₀ ≤ 50 μM) and selectivity index (SI ≥ 1.25), 18 ligands were identified as active and selective among the screened compounds. These findings highlight promising candidates with potential antiproliferative activity, outperforming the reference drug sorafenib under the applied selection criteria. Compound 6b (0.21 μM) exhibited excellent inhibitory activity on VEGFR-2 compared to sorafenib (0.30 μM). Antioxidant activity investigated by DPPH scavenging method depicted that compound 5b had strong antioxidant activity with IC₅₀ value of 11.17 μM. The most potent compound 5b exerted cell cycle arrest. The apoptotic activity of designed compounds was evaluated through determination their ability to activate caspases 3,7 and 9 and especially compounds 5a and 5b showed promising conduction of these enzymes and apoptosis. Molecular modeling studies on VEGFR-2, molecular dynamic simulations and DFT calculations gave good insight to identify the difference of potential inhibition against the different cell lines.