Abstract
Cryptosporidium parvum has a salvaged guanine nucleotide biosynthetic pathway for metabolism in which inosine-5’-monophosphate dehydrogenase (IMPDH) plays a key role. The characterization of C. parvum IMPDH has instigated a drug discovery program exploiting a nicotinamide adenine dinucleotide (NAD+) active site for selective inhibition over its human counterpart. A series of N-aryl-4-oxophthalazine acetamide inhibitors are described. For acyclic substituted anilines, structure-activity relationship revealed that electron-withdrawing substituents at the para-position are required. An additional substituent in the meta-position improved potency up to 10-fold. It was proposed that pseudo-ring formation due to π-π interactions of substituents at the 3- and 4- positions of the aniline ring may be inducing enzyme inhibition. Further optimization utilizing the pseudo-ring hypothesis has resulted in the discovery of new benzofuranamide analogs exhibiting low nanomolar enymatic inhibition against CpIMPDH, and low nanomolar minimum inhibitory concentration against the fatal disease-causing biowarfare bacteria Franciscella tularensis.