Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

Kokkonda, Sreekanth; Deng, Xiaoyi; White, Karen L.; Coteron, Jose M.; Marco, Maria; de las Heras, Laura; White, John; El Mazouni, Farah; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Chen, Gong; Morizzi, Julia; Ryan, Eileen; Kaminsky, Werner; Leroy, Didier; Martínez-Martínez, María Santos; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Waterson, David; Burrows, Jeremy N.; Matthews, Dave; Charman, Susan A.; Phillips, Margaret A.; Rathod, Pradipsinh K.

doi:10.1021/acs.jmedchem.6b00275

Title: Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

Journal Article · Fri Apr 29 00:00:00 EDT 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b00275· OSTI ID:1267477

Kokkonda, Sreekanth ^[1]; Deng, Xiaoyi ^[2]; White, Karen L. ^[3]; Coteron, Jose M. ^[4]; Marco, Maria ^[4]; de las Heras, Laura ^[4]; White, John ^[1]; El Mazouni, Farah ^[2]; Tomchick, Diana R. ^[2]; Manjalanagara, Krishne ^[5]; Rudra, Kakali Rani ^[5]; Chen, Gong ^[3]; Morizzi, Julia ^[3]; Ryan, Eileen ^[3]; Kaminsky, Werner ^[1]; Leroy, Didier ^[6]; Martínez-Martínez, María Santos ^[4]; Jimenez-Diaz, Maria Belen ^[4]; Bazaga, Santiago Ferrer ^[4]; Angulo-Barturen, Iñigo ^[4] more »

Univ. of Washington, Seattle, WA (United States)
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Monash Univ., Parkville, VIC (Australia)
GSK, Madrid (Spain)
Syngene International Ltd., Bangalore (India)
Medicines for Malaria Venture, Geneva (Switzerland)

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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health

Grant/Contract Number:: R01AI103947; U01AI075594

OSTI ID:: 1267477

Journal Information:: Journal of Medicinal Chemistry, Vol. 59, Issue 11; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 41 works

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A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria Phillips, Margaret A.; White, Karen L.; Kokkonda, Sreekanth ACS Infectious Diseases, Vol. 2, Issue 12 https://doi.org/10.1021/acsinfecdis.6b00144	journal	October 2016

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Title: Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

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