Discovery of novel imidazo[2,1-b]thiazole-hydrazone hybrids as multi-target anticancer agents: Dual PARP-1/COX-2...

In the present study, a series of novel imidazo[2,1-b]thiazole hydrazone hybrids bearing a 4-fluorophenyl moiety (4a-m) were designed and synthesized. Their structural characterization and purity analyses were performed using analytical and spectral methods (FT-IR, ¹H NMR, ¹³C NMR (APT), and elemental analysis). The cytotoxic properties of compounds 4a-m were evaluated against human neuroblastoma SH-SY5Y and HEK293 cells using MTT assays. Compound 4b was found to be the most promising derivative, with an IC₅₀ value of 2.96 μM against SH-SY5Y cells and an SI value of 16.9, indicating promising efficacy and selectivity. All compounds were also investigated for their enzyme inhibition activities against COX-1, COX-2, PARP-1, and MetAP-2. In terms of COX inhibition, compound 4d was the most potent COX-2 inhibitor with an inhibition rate of 75.8%. Additionally, compounds 4c, 4g, 4h, and 4i exhibited comparable PARP-1 inhibition to the standard olaparib in the range of 94.9-99.0%. Evaluation of MetAP-2 levels revealed that compound 4e markedly reduced enzyme levels in SH-SY5Y cells. To elucidate the structural basis of these activities at the atomic level, comprehensive molecular docking and 300 ns molecular dynamics (MD) simulations were conducted. Notably, MD trajectories unveiled a flawless (100% persistent) direct metal coordination between compound 4e and the catalytic Co²⁺ ion of MetAP-2, alongside highly stable, target-specific anchoring networks for the COX-2/4d and PARP-1/4i complexes. Furthermore, the in silico drug-likeness profiles of the compounds were assessed according to Lipinski's Rule of Five (RO5), revealing excellent oral absorption potentials. Overall, these findings highlight imidazo[2,1-b]thiazole hydrazone hybrids as promising multi-target scaffolds for the development of novel anticancer agents.