Le Manach, CPaquet, TWicht, KNchinda, A.TBrunschwig, CNjoroge, MGibhard, LTaylor, DLawrence, NWittlin, SEyermann, C.JBasarab, G.SDuffy, JFish, P.VStreet, L.JChibale, K2024-08-032024-08-032018-10-25Le Manach C, Paquet T, Wicht K, Nchinda AT, Brunschwig C, Njoroge M, Gibhard L, Taylor D, Lawrence N, Wittlin S, Eyermann CJ, Basarab GS, Duffy J, Fish PV, Street LJ, Chibale K. Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space To Circumvent Atypical Dose-Response Curves against Multidrug Resistant Parasite Strains. J Med Chem. 2018 Oct 25;61(20):9371-9385. doi: 10.1021/acs.jmedchem.8b01333.10.1021/acs.jmedchem.8b01333https://pubmed.ncbi.nlm.nih.gov/30256636/https://hdl.handle.net/11288/597107A 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.enArticle