Design, synthesis, biological evaluation, and in silico studies of 2-aminobenzothiazole derivatives as potent PI3Kα inhibitors

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an 10 50 value of 6.34 mu M and compound 8m displayed an IC50 value of 8.30 mu M against the MCF7 cell line compared to the standard drug HS-173 (IC50 = 10.25 mu M). P13K enzyme activity assays demonstrated that compound 8i is highly selective against PI3K alpha, with an IC50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the P13K inhibitory activity of compound 8i. The molecular docking and molecular dynamics simulation studies performed were found in agreement with the PI3K alpha inhibitory activity assessments performed experimentally.

Automated summary

A series of 2-aminobenzothiazole derivatives were synthesized and evaluated for their anticancer activity. Compound 8i showed the most potent inhibitory activity and high selectivity against PI3K alpha, inducing apoptosis in a dose-dependent manner.