Abstract
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 (KIs in the range of 1.0–705.5 nM), and IX (KIs 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.
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•Piperazinylureido aryl sulfamates were designed and synthesized.•Sulfamates were assayed in vitro as human Carbonic Anhydrase (CA) isoforms inhibitors.•Synthesized compounds show weak activity against off-target CA I and CA IV isoforms.•Some sulfamates are CA II/IX selective inhibitors representing leads for the development of new anticancer agents.•Docking revealed that CA-selective inhibition is related to distinguished interactions.