Synthesis, anti-proliferative activity, gene expression, docking and DFT investigation of novel Pyrazol-1-yl-thiazol-4(5H)-one derivatives

Abstract In this elucidation, the novel thaizolone derivatives 8a-n were synthesised via the reaction between thioamide derivatives 4a, b with chloroacetic acid and the appropriate aldehyde derivatives 7a-g in acetic acid. The molecular structures of these two were confirmed via different spectral analyses. The thaizolone derivatives 8a-n were investigated via DFT/ B3LYP/6-31G (d) level and compared their energies and physical characterizations, which showed the most stable compounds from biphenyl and phenyl-piperidine fused thiazolone rings were 8f and 8m. The compounds 8f and 8m were exhibited as anti-proliferative compounds against MCF-7 breast cancer and PC-3 prostate cancer cells via the MTT experiment. Compound 8f showed more inhibitory influence on MCF-7 growth, while compound 8m revealed more cytotoxicity in PC-3 cells. The results were confirmed through a morphology study, where the expression levels of BCL2, Cyclin D1, FGF1 and HIF1α genes were examined by QRT-PCR. This study showed that compounds 8f and 8m exhibited important pro-apoptotic effects, concluding the down regulation of BCl-2 and CCND1 genes. Also, the anti-angiogenic effect of compound 8f emerged due to the downregulation of FGF1 expression stages and the upregulation of HIF-1α. The stability and structural properties of the predicted conformers were studied using DFT theoretical calculations, which demonstrated that the stability of the anticipated conformers is affected by the configuration of the biphenyl and phenyl pipridine moieties in the synthesised thiazolone. Furthermore, the docking structures of these compounds 8f and 8m were investigated by (PDBID:4hdq), (PDBID:3ruk), (PDBID:5jsn) and (PDBID:5VZU) which confirmed the experimental results and showed the stability of 8f rather than 8m due to the presence of biphenyl and made more conjugation.