Design, synthesis, docking study, cytotoxicity evaluation, and PI3K inhibitory activity of Novel di-thiazoles, and bis(di-thiazoles)

Abstract

A series of novel thiazole hybrids were designed and synthesized using a molecular hybridization approach to develop more potent Pi3k inhibitors for cancer treatment. As a result of the reaction of (phenylthiazol-5-yl)ethylidenehydrazine-1-carbothioamide with the corresponding bis-bromoacetyl derivatives, reasonable yields of novel bis-dithiazoles linked via aliphatic, aromatic, or heterocyclic cores were obtained. The structural details of the new compounds were confirmed using spectral data and elemental analysis. All of the proposed compounds were molecularly docked based on their structural similarity to the alpelisib pi3k inhibitor, and compounds 11e and 11d demonstrated very good binding modes that ranged between hydrogen and pi bonds. All compounds were tested for anticancer activity against HT29 colon cancer cells. The IC50 values for compounds 11d and 11e were 4.4 and 8.3 nM, respectively. In addition, PI3K enzyme inhibition activity was assessed, and the results ranged from very low IC50 for 11e and 11d, which revealed 2.33 and 2.55 nM, to moderate for 11b, 11c, 13b, and 15b, with IC50 of 7.58, 6.15, 7.9, and 9.11 nM, respectively, when compared to alpelisib, which revealed an IC50 of 4.96 nM. The inhibitory activity of the most potent compounds was qualitatively evaluated by Western Blotting, and pi3k gene expression was found to be inhibited to half of its maximum value.