ABSTRACT
Cancer is a major global health concern, and the constant search for novel, selective anticancer compounds with low toxicity is never ending. Nitrogen heterocyclic compounds such as pyrimidine and triazole have been identified as potential candidates for cancer treatment. A novel series of 1,2,3-triazole incorporated thiazole-pyrimidine-isoxazole derivatives 10 (a-j) were designed, synthesized and evaluated for antitumorigenic activities against human breast cancer (MCF-7), human lung cancer (A549) and human prostate (PC3 & DU-145) various cell-lines by employing MTT assay using etoposide as the positive control. The synthesized hybrids yielded decent efficacy, which was further compared with the standard drug. Among all the molecules, 10h revealed the more potent anticancerous activities, having IC50 values ranging from 0.011 ± 0.0017 µM; 0.063 ± 0.0012 µM; 0.017 ± 0.0094 µM and 0.66 ± 0.072 µM with DU145, PC3, A549, and MCF7 cell-lines, respectively. Tubulin, being a major protein involved with diverse biological actions, also serves, as a crucial target for several clinically practiced anticancer drugs, was utilized for docking analyses to evaluate the binding affinity of ligands. Docking results demonstrates that the selected hybrids 10 (g-j) exhibited good binding affinities with protein. Subsequently, drug likeness studies were carried out on the synthesized compounds to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Based on these analyses, the selected complexes were further employed for molecular dynamic simulations to analyze stability via an exhaustive cumulative 200 nanoseconds simulation. These results suggest that the selected compounds are stable and might serve as potential inhibitors to tubulin complex. In conclusion, we propose these synthesized compounds 10 (g-j) might provide new insights into cancer treatment and have potential for future development.Communicated by Ramaswamy H. Sarma.
