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

Abstract

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.

Authors:
 [1];  [2];  [3];  [4];  [4];  [4];  [1];  [2];  [2];  [5];  [5];  [3];  [3];  [3];  [1];  [6];  [4];  [4];  [4];  [4] more »;  [6];  [6];  [6];  [3];  [2];  [1] « less
  1. Univ. of Washington, Seattle, WA (United States)
  2. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  3. Monash Univ., Parkville, VIC (Australia)
  4. GSK, Madrid (Spain)
  5. Syngene International Ltd., Bangalore (India)
  6. Medicines for Malaria Venture, Geneva (Switzerland)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Inst. of Health
OSTI Identifier:
1267477
Grant/Contract Number:  
R01AI103947; U01AI075594
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 11; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; anatomy; assays; rodent models; inhibition; parasites

Citation Formats

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., and Rathod, Pradipsinh K. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b00275.
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. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity. United States. https://doi.org/10.1021/acs.jmedchem.6b00275
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., and Rathod, Pradipsinh K. 2016. "Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity". United States. https://doi.org/10.1021/acs.jmedchem.6b00275. https://www.osti.gov/servlets/purl/1267477.
@article{osti_1267477,
title = {Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity},
author = {Kokkonda, Sreekanth and Deng, Xiaoyi and White, Karen L. and Coteron, Jose M. and Marco, Maria and de las Heras, Laura and White, John and El Mazouni, Farah and Tomchick, Diana R. and Manjalanagara, Krishne and Rudra, Kakali Rani and Chen, Gong and Morizzi, Julia and Ryan, Eileen and Kaminsky, Werner and Leroy, Didier and Martínez-Martínez, María Santos and Jimenez-Diaz, Maria Belen and Bazaga, Santiago Ferrer and Angulo-Barturen, Iñigo and Waterson, David and Burrows, Jeremy N. and Matthews, Dave and Charman, Susan A. and Phillips, Margaret A. and Rathod, Pradipsinh K.},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.6b00275},
url = {https://www.osti.gov/biblio/1267477}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 11,
volume = 59,
place = {United States},
year = {Fri Apr 29 00:00:00 EDT 2016},
month = {Fri Apr 29 00:00:00 EDT 2016}
}

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Works referencing / citing this record:

A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria
journal, October 2016