Structure guided modification of 2-chloro-5-(ethyl-phenyl-sulfamoyl)-N-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide to afford selective inhibitors of Cryptosporidium parvum N-myristoyltransferase

Cryptosporidium parvum is a protozoan parasite that causes severe diarrheal illness in children and each year nearly 50,000 children under age 5 die due to the disease. Despite tremendous research efforts, there remains a lack of effective therapies and vaccines. Novel inhibitors against N-myristoyltransferase of C. parvum (CpNMT) are potential starting points towards the development of effective therapies. In quest of promising selective CpNMT inhibitors, structure guided modifications of compound 1 (2-chloro-5-(ethyl-phenyl-sulfamoyl)-N-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide) were performed. The resulting compounds were evaluated for selective inhibition of CpNMT over the host enzyme HsNMT1. Compounds 11e and 11f exhibited good inhibition, with IC₅₀ values of 2.5 and 2.8 μM, respectively. While 11e was slightly more selective towards CpNMT over HsNMT1 (∼5-fold), compound 11f showed >40-fold selectivity, validating our structure-based design approaches. Compounds 11e and 11f were also found to be efficacious against C. parvum growth, with EC₅₀ values of 6.9 and 16.4 μM, respectively.