Le Manach, C;
Paquet, T;
Wicht, K;
Nchinda, AT;
Brunschwig, C;
Njoroge, M;
Gibhard, L;
... Chibale, K; + view all
(2018)
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.
Journal of Medicinal Chemistry
, 61
(20)
pp. 9371-9385.
10.1021/acs.jmedchem.8b01333.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | 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 |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.jmedchem.8b01333 |
| Publisher version: | http://doi.org/10.1021/acs.jmedchem.8b01333 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | antiplasmodial activity, atypical dose-response curves, chemical space, permeability, pharmacokinetics. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10060473 |
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