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. 2025 Apr 15:119:130092.
doi: 10.1016/j.bmcl.2025.130092. Epub 2025 Jan 6.

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

Dilep K Sigalapalli  1 , Sophia Groustra  2 , Michael K Fenwick  2 , Rachael Zigweid  2 , Matthew A Hulverson  3 , Eric Owsley  1 , Monique Khim  2 , Sayaka Shibata  1 , Wesley C Van Voorhis  3 , Bart L Staker  4 , Erkang Fan  5
Affiliations

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

Dilep K Sigalapalli et al. Bioorg Med Chem Lett. .

Abstract

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.

Keywords: Cryptosporidiosis; N-Myristoyltransferase; Selectivity.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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