Synthesis and structure-affinity relationship of chlorinated pyrrolidinone-bearing benzenesulfonamides as human carbonic anhydrase inhibitors.

ABSTRACT

A novel set of pyrrolidinone-based chlorinated benzenesulfonamide derivatives were synthesized and investigated for their binding affinity and selectivity against recombinant human carbonic anhydrases I-XIV using fluorescent thermal shift, p-nitrophenyl acetate hydrolysis and stopped-flow enzymatic inhibition assays. The hydrazones 10-22 prepared from 1-(2-chloro-4-sulfamoylphenyl)-5-oxopyrrolidine-3-carboxylic acid exhibited low nanomolar affinity against cancer-related CA IX (Kd in the range of 5.0-37 nM). Compounds with triazole or oxadiazole groups attached directly to pyrrolidinone moiety bound all CAs weaker than compounds with more flexible tail groups. Chloro group at the meta position of benzenesulfonamide derivatives increased affinity to all CAs as compared with binding data for nonchlorinated compounds. The compounds have a potential for further development of CA inhibitors with higher selectivity for a particular CA isozyme.