Binding Mode and Potency of <i>N</i>‑Indolyloxopyridinyl-4-aminopropanyl-Based Inhibitors Targeting <i>Trypanosoma cruzi</i> CYP51

Abstract

Chagas disease is a chronic infection in humans caused by <i>Trypanosoma cruzi</i> and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with <i>T. cruzi</i> worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in <i>T. cruzi</i>. We report the structure–activity relationships (SAR) of an <i>N</i>-arylpiperazine series of <i>N</i>-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95–2.48 Å). The 5-chloro-substituted analogs <b>9</b> and <b>10</b> with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days