Design, synthesis, and biological investigation of selective human carbonic anhydrase II, IX, and XII inhibitors using 7-aryl/heteroaryl triazolopyrimidines bearing a sulfanilamide scaffold.

A novel library of human carbonic anhydrase (hCA) inhibitors based on the 2-sulfanilamido[1,2,4]triazolo[1,5- a ]pyrimidine skeleton modified at its 7-position was prepared by an efficient convergent procedure. These derivatives were evaluated in vitro for their inhibition properties against a representative panel of hCA isoforms (hCA I, II, IV, IX, and XII). The target tumour-associated isoforms hCA IX and XII were potently inhibited with K I s in the low nanomolar range of 5-96 nM and 4-72 nM, respectively. Compounds 1d , 1j , 1v , and 1x were the most potent hCA IX inhibitors with K I s of 5.1, 8.6, 4.7, and 5.1 nM, respectively. Along with derivatives 1d and 1j , compounds 1r and 1ab potently inhibited hCA XII isoform with K I s in a single-digit nanomolar range of 8.8, 5.4, 4.3, and 9.0 nM, respectively. Compounds 1e , 1m , and 1p exhibited the best selectivity against hCA IX and hCA XII isoforms over off-target hCA II, with selectivity indexes ranging from 5 to 14.