Design, synthesis, and biological evaluation of novel thiazole derivatives as PI3K/mTOR dual inhibitors

The development of anticancer drugs targeting both PI3K and mTOR pathways is recognized as a promising cancer therapeutic approach. In the current study, we designed and synthesized seventeen new thiazole compounds to investigate their effect on both PI3K and mTOR as well as their anti-apoptotic activity. All the synthesized thiazoles were investigated for their antiproliferative activity on a panel of 60 different cancer cell lines at the National Cancer Institute. Compounds 3b and 3e were selected for further investigation at five dose concentrations due to their effective growth inhibiting activity. Compounds 3b and 3e were further evaluated for their in vitro inhibitory activities against PI3K alpha and mTOR compared to alpelisib and dactolisib, respectively as reference drugs. The inhibitory effect of compound 3b on PI3K alpha was similar to alpelisib, but it showed weaker inhibitory activity on mTOR compared to dactolisib. Moreover, compound 3b exhibited significantly higher inhibitory activity compared to compound 3e against both PI3K alpha and mTOR. The cell cycle analysis showed that compounds 3b and 3e induced G0-G1 phase cell cycle arrest in the leukemia HL-60(TB) cell line. Meanwhile, they significantly increased the total apoptotic activity which was supported by an increase in the level of caspase-3 in leukemia HL-60(TB) cell lines. Molecular docking experiments provided additional explanation for these results by demonstrating the ability of these derivatives to form a network of key interactions, known to be essential for PI3K alpha/mTOR inhibitors. All these experimental results suggested that 3b and 3e are potential PI3K alpha/mTOR dual inhibitors and could be considered promising lead compounds for the development of anticancer agents. A series of new thiazole derivatives 3a-q were synthesized and tested against 60 cancer cell lines at the NCI, USA. Compound 3b showed the highest activity against PI3K alpha with IC50 = 0.086 +/- 0.005 mu M and IC50 of 0.221 +/- 0.014 mu M against mTOR.