Appliance of the piperidinyl-hydrazidoureido linker to benzenesulfonamide compounds: Synthesis, in vitro and in silico evaluation of potent carbonic anhydrase II, IX and XII inhibitors

Herein we report on a new series of hydrazidoureidobenzensulfonamides investigated as inhibitors of the cytosolic human (h) hCA I and II isoforms, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The reported derivatives contain a 4-substituted piperidine fragment in which the hydrazidoureido linker has been involved as spacer between the benzenesulfonamide fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Depending on the substitution pattern at the piperidine ring, low nanomolar inhibitors were detected against hCA II, hCA IX and hCA XII, making the new class of sulfonamides of interest for various pharmacologic applications.