Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

Abstract

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

Nitroimidazopyrazinones with oral activity against tuberculosis and Chagas disease in mouse models of infection

“…These compounds completely cleared parasites (100%) from 3T3 host cells at E max concentrations (maximal activity achievable in dose-response curves, Fig 6), in contrast to the CYP51 inhibitor, posaconazole that showed 87% inhibition at E max . This phenotypic characteristic suggested that MCC9481 and MCC9482 might not inhibit the CYP enzyme, consistent with other bicyclic nitroimidazole analogs that were reported to be inactive against CYP51 [21].…”

“…The repurposing potential of delamanid and pretomanid analogs for the treatment of kinetoplastid diseases [18, 20, 21] led us to investigate the antitrypansomal activity of nitroimidazopyrazinones against T. cruzi . Initial investigations using high content imaging demonstrated that analogs with extended biaryl side chains were highly active against T. cruzi (IC 50 = 0.016–4.2 µM) [35].…”

“…They were later found to have repurposing potential against visceral leishmaniasis (VL) [18, 19], which is caused by the kinetoplastid protozoan, Leishmania . Through a collaborative program between the University of Auckland, TB Alliance, and DND i , a backup library of 900 pretomanid analogs have been counter-screened against Trypanosoma brucei and T. cruzi, resulting in the discovery of several promising hits to be pursued [20, 21].…”

Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

“…According to Vermelho et al, it is a disease considered neglected and few drugs are being developed for the treatment of CD with no progress in this direction since the 1960s [6]. Regarding the discovery of new drugs for CD, the strategy of target-based drug discovery was hampered by the lack of targets well validated [7]. According to Pérez-Molina and Molina, in the area of drug development, existing animal models are limited because they have a poor translation of in vivo data [8].…”

“…Therefore, according to the authors, it is necessary to standardize new animal models capable of more safely predicting the effectiveness of new drug candidates [8]. According to Thompson et al, the phenotypic screening of libraries with several compounds is still considered the best strategy to identify new leads or starting points [7]. Moreover, the discovery of new drugs for Chagas disease need collaborative networks involving academia, pharmaceutical companies, government organs and entities such as DNDi (Drugs for Neglected Diseases initiative), all of them contributing for substantial advances where actions must be as synergistic as possible in order to support the translation of academic research into available drugs [9,10].…”