Pyrimido[5,4-e]azolo[1,5-a]pyrimidines and pyrimido[4,5-e][1,2,4]triazolo[5,1-c][1,2,4]triazines: one-pot multi-component synthesis and cytotoxic activity

Abstract

A multi-component one-pot method for the synthesis of pyrimido[5,4-e]azolo[1,5-a]pyrimidines and pyrimido[4,5-e][1,2,4]triazolo[5,1-c][1,2,4]triazines has been developed. It was shown that vicinal amino-nitrile and amino-ethoxycarbonyl derivatives of azolo[1,5-a]pyrimidines and azolo[5,1-c][1,2,4]triazines were converted to tricyclic heterocycles in the “AcOH–RC(OEt)₃–amine” system. Reaction conditions were optimized, patterns of this process were investigated, and intermediates were isolated. The observed details revealed the plausible mechanism, which starts with the attack of the amine on the electron-deficient carbon atom of the ester or nitrile group. The cytotoxic activity of the obtained heterocycles was studied on the cell lines Hep-G2, A-172, A-549, HEK-293 and a lead compound with IC₅₀ in the mid-micromolar range was identified.