Novel thiazolone-benzenesulphonamide inhibitors of human and bacterial carbonic anhydrases

A small library of novel thiazolone-benzenesulphonamides has been prepared and evaluated for their ability to inhibit three human cytosolic carbonic anhydrases (hCA I, hCA II, and hCA VII) and three bacterial carbonic anhydrases (MscCA beta, StCA1, and StCA2). All investigated hCAs were inhibited by the prepared compounds 4a-4j in the low nanomolar range. These compounds were effective hCA I inhibitors (K(I)s of 31.5-637.3 nM) and excellent hCA II (K(I)s in the range of 1.3-13.7 nM) and hCA VII inhibitors (K(I)s in the range of 0.9-14.6 nM). The most active analog in the series, 4-((4-oxo-5-propyl-4,5-dihydrothiazol-2-yl)amino)benzenesulphonamide 4d, strongly inhibited bacterial MscCA beta, with K-I of 73.6 nM, considerably better than AAZ (K-I of 625 nM). The tested compounds displayed medium inhibitory potency against StCA1 (K(I)s of 69.2-163.3 nM) when compared to the standard drug (K-I of 59 nM). However, StCA2 was poorly inhibited by the sulphonamides reported here, with K(I)s in the micromolar range between 275.2 and 4875.0 nM.

Automated summary

A library of novel thiazolone-benzenesulphonamides was synthesized and evaluated for their inhibitory activity against human cytosolic carbonic anhydrases and bacterial carbonic anhydrases. The prepared compounds 4a-4j showed low nanomolar range inhibition against all investigated hCAs. Compound 4d exhibited strong inhibition against bacterial MscCA beta with a K-I of 73.6 nM, much better than AAZ. The tested compounds showed medium inhibitory potency against StCA1 compared to the standard drug, while poorly inhibited StCA2.