We report here a thorough structure-activity relationship (SAR) with piperazinylureido sulfamates as inhibitors of human (h) carbonic anhydrase (CA, EC 4.2.1.1). A SAR investigation over the structure of reported anti-cancer zinc-binder CAIs such as SLC-0111 and S4 was carried out by including the urea outer nitrogen atom into a substituted piperazine ring reducing the linker flexibility. The derivatives were assessed for the inhibition of CA I, II and IV (off-target isoforms) and the tumor-associated CA IX (anticancer drug target). CA I and IV were not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against CA II (Ks in the range of 1.0-705.5 nM), and IX (Ks in the range of 0.91-155.9 nM). Interestingly, a subset of CA II/IX selective inhibitors was detected which might represent interesting lead for the development of new anticancer strategies.