Synthesis and molecular modeling studies of new thiohydantoin-triazole hybrids as anticancer agents

The targeted thiohydantoin-triazole hybrid compounds 5a-d and 9a-d were synthesized by the copper-catalyzed click reaction of 2-azido-N-arylacetamides 3a-d with the appropriate alkynes, thiohydantoin moiety linked to a propargyl group. Molecular modelling of the prepared hybrids at DFT/B3LYP/6–311++G(d,p) divulged comparable non-planar configurations of 5a-d, while V-like configurations were observed for derivatives 9a-d. Except for nitrophenyl derivatives 5 d and 9 d, whose LUMO was focused on the N-nitrophenyl acetamide branch, the analogues showed identical configurations of their FMOs, π-, and π*-orbitals of the imidazolidinylidene moiety.Additionally, using the MTT assay, the synthesized hybrids’ in vitro cytotoxic efficacy towards diverse malignant cell of the was evaluated. The conjugate 9b exhibited distinguished cytotoxic efficiency and the highest selectivity index against the examined cell lines, with IC50 (μM) = 10.30 ± 0.21 for HepG2, 13.73 ± 0.10 for HT-29 and 7.85 ± 0.05 for MCF-7. As a result, thiohydantoin-triazole 9b may be promising candidates for further anticancer drug development. In contrast to the reference drug Dasatinib, some of the synthesized hybrids displayed effective cytotoxic effects with selectivity against some cancer cells. Moreover, the potential of hybrids 5 and 9 as bioactive ligands has been assessed using molecular docking, in comparison to the Dasatinib, where the hybrid 9 d displayed the highest binding energy followed by 9c and 9b. Additionally, the pharmacokinetic properties of the newly prepared compounds were evaluated using SwissADME estimates and they exhibited variable degrees of solubility, GI-absorption, and potential for passive diffusion, especially, hybrids 5a, 5c, and 8.