Design, synthesis, biological assessment, and in-Silico studies of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives have been designed and synthesized as combretastatin CA-4 analogs. They were screened for Anticancer and tubulin polymerization inhibition activities. The trimethoxyphenyl 1,2,4-triazolo[1,5-a]pyrimidine derivative 4c showed significant antiproliferative activity in which it exhibited IC₅₀ = 0.53 μM against HCT-116 Cancer cell line. It was further tested as a tubulin polymerization inhibitor showing an IC₅₀ = 3.84 μM if compared to combretastatin IC₅₀ = 1.10 μM. Further mechanism studies revealed that compound 4c could obviously inhibit the proliferation of HCT-116 Cancer cells by inducing Apoptosis and arresting the cell cycle at the G₂/M phase. Furthermore, docking studies showed that compound 4c illustrated good fitting to the colchicine binding site of tubulin. Thus, it is considered an Anticancer lead compound worthy of further development as a tubulin polymerization inhibitor.