Abstract:
Visceral leishmaniasis (VL) is a fatal sandfly-borne disease that is caused by the parasites Leishmania donovani (Indian subcontinent, Eastern Africa) and Leishmania infantum (Latin America, Central Asia, and Mediterranean region). The few available treatment options for VL all suffer from various drawbacks and there is an urgent need for affordable, short-course oral drugs with enhanced safety and efficacy (especially in Eastern Africa). Bicyclic nitroimidazole derivatives were initially explored by us, as part of an anti-tuberculosis drug development program with the TB Alliance. Phenotypic screening of selected early examples by DNDi and follow-up in vivo assessment led to the rapid identification of nitroimidazooxazole 1 as a preclinical candidate for VL. A collaborative backup project between Auckland University and DNDi was then launched to investigate two related nitroimidazooxazine classes derived from the drug pretomanid (2). More than 330 new analogues were prepared, including over 100 in the promising 7-substituted class, seeking to optimally balance physicochemical and pharmacokinetic properties, efficacy, and safety. When 1 failed to meet all of the criteria for clinical evaluation, two excellent backup candidates (DNDI-8219, 3 and DNDI-0690, 4) were assessed in a 14 day rat toxicity study, and the latter was selected for advanced development. Structure-activity relationships and several new results will be presented.
