TY - JOUR
T1 - Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice
AU - Gujjar, Ramesh
AU - El Mazouni, Farah
AU - White, Karen L.
AU - White, John
AU - Creason, Sharon
AU - Shackleford, David M.
AU - Deng, Xiaoyi
AU - Charman, William N.
AU - Bathurst, Ian
AU - Burrows, Jeremy
AU - Floyd, David M.
AU - Matthews, David
AU - Buckner, Frederick S.
AU - Charman, Susan A.
AU - Phillips, Margaret A.
AU - Rathod, Pradipsinh K.
PY - 2011/6/9
Y1 - 2011/6/9
N2 - Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance.We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF5-Ph and 3,5-Di-F-4- CF 3-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.
AB - Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance.We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF5-Ph and 3,5-Di-F-4- CF 3-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.
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U2 - 10.1021/jm200265b
DO - 10.1021/jm200265b
M3 - Article
C2 - 21517059
AN - SCOPUS:79958100876
SN - 0022-2623
VL - 54
SP - 3935
EP - 3949
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -