by Thompson AM, O’Connor PD, Yardley V, Maes L, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, Denny WA. ACS Medicinal Chemistry Letters 2021, 12, 2, 275–281. doi: 10.1021/acsmedchemlett.0c00649
Summary: Antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, and lead optimization culminated in a new clinical investigational drug for visceral leishmaniasis: DNDI-0690. Given the high attrition rate for small molecules in clinical development, this study aimed to discover novel backup candidates with divergent candidate profiles, especially analogues possessing greater aqueous solubility. 32 analogues were prepared, including an O-carbamate which had the best balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong in vivo efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg).