Evaluation of dipeptide nitriles as inhibitors of rhodesain, a major cysteine protease of Trypanosoma brucei.

摘要: A series of dipeptide nitriles known as inhibitors mammalian cathepsins were evaluated for inhibition rhodesain, the cathepsin L-like protease Trypanosoma brucei. Compound 35 consisting a Leu residue fitting into S2 pocket and triarylic moiety thiophene, 1,2,4-oxadiazole phenyl ring S3 pocket, compound 33 with 3-bromo-Phe (S2) biphenyl fragment (S3) found to inhibit rhodesain in single-digit nanomolar range. The observed steep structure-activity relationship could be explained by covalent docking simulations. With their high selectivity indices (ca. 200) good antitrypanosomal activity (8μM) compounds represent promising starting points new inhibitors.