Synthesis and molecular modeling of new triazole-oxadiazole and triazole-thiadiazole compounds as cytotoxic agents

New triazole-oxadiazole and triazole-thiadiazole hybrid compounds 5, 8, and 9 were synthesized from the building block, triazole-4-carbohydrazide compound 2 by different synthetic strategies. The DFT/B3LYP modeling of the built hybrids released a non-planar configuration. The analogues 2 and 3 presented comparable HOMO-LUMO formation and covered the full skeleton. (π- and π*-orbitals, respectively); however, the other derivatives presented alternative designs. However, an in vitro cytotoxic activeness of the produced triazole-oxadiazole and triazole-thiadiazole compounds was assessed; hybrids 5a, 7a, and 9a showed eminent cytotoxicity against both HT-29 and MCF-7 cancer cells. While hybrid 9a established the potent effectiveness against HT-29 cells (IC₅₀ = 13.52±0.49 μM), nearing the efficacy of doxorubicin (reference). Through molecular docking analysis, hybrid 5a showed the strongest binding affinity (S = -7.4059 kcal/mol), comparable to the reference doxorubicin. Key interactions included hydrogen bonding, π-cation, and π-H stacking involving crucial residues in the target protein’s pocket. Furthermore, the pharmacokinetic profiles of ten novel hybrids revealed that hybrids 2, 3, 7a, 8a, 8b, and 9a showed the finest pharmacokinetic behaviors, counting high gastrointestinal absorption (GI) absorption, without blood brain barrier (BBB) permeability, and bioavailability scores (0.55), while hybrids 5b, 7b, and 9b exhibited minor deviations due to elevated topological polar surface area (TPSA) or Lipinski violations, possibly preventing their CNS and oral bioavailability.