TY - JOUR
T1 - Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity
AU - Kokkonda, Sreekanth
AU - Deng, Xiaoyi
AU - White, Karen L.
AU - Coteron, Jose M.
AU - Marco, Maria
AU - De Las Heras, Laura
AU - White, John
AU - El Mazouni, Farah
AU - Tomchick, Diana R.
AU - Manjalanagara, Krishne
AU - Rudra, Kakali Rani
AU - Chen, Gong
AU - Morizzi, Julia
AU - Ryan, Eileen
AU - Kaminsky, Werner
AU - Leroy, Didier
AU - Martínez-Martínez, María Santos
AU - Jimenez-Diaz, Maria Belen
AU - Bazaga, Santiago Ferrer
AU - Angulo-Barturen, Iñigo
AU - Waterson, David
AU - Burrows, Jeremy N.
AU - Matthews, Dave
AU - Charman, Susan A.
AU - Phillips, Margaret A.
AU - Rathod, Pradipsinh K.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/6/9
Y1 - 2016/6/9
N2 - Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.
AB - Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.
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U2 - 10.1021/acs.jmedchem.6b00275
DO - 10.1021/acs.jmedchem.6b00275
M3 - Article
C2 - 27127993
AN - SCOPUS:84974560565
SN - 0022-2623
VL - 59
SP - 5416
EP - 5431
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -