Novel Linker Variants of Antileishmanial/Antitubercular 7-Substituted 2-Nitroimidazooxazines Offer Enhanced Solubility.

Abstract

Antitubercular 7-substituted 2-nitroimidazo[2,1-<i>b</i>][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated <i>in vitro</i> and <i>in vivo</i> but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold. Ultimately, we discovered that <i>O</i>-carbamate <b>66</b> offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong <i>in vivo</i> efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg).