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Antimalarial Lead-Optimisation Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space To Circumvent Atypical Dose−Response Curves against Multidrug Resistant Parasite Strains

Wednesday, 24 October 2018 07:58
Claire Le Manach

This paper appeared in Journal of Medicinal Chemistry, September 26, 2018.


A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose–response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose–response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.

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This article is taken from Journal of Medicinal Chemistry, September 26, 2018. Copyright © American Chemical Society.

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Last Updated on Monday, 29 October 2018 09:36