Tetrahydro-2-naphthyl and 2-Indanyl triazolopyrimidines targeting Plasmodium falciparum Dihydroorotate Dehydrogenase display potent and selective antimalarial activity

Sreekanth Kokkonda, Xiaoyi Deng, Karen L White, Jose M Coteron, Maria Marco, Laura de las Heras, John White, Farah El Mazouni, Diana R Tomchick, Krishne Manjalanagara, Kakali Rani Rudra, Gong Chen, Julia Morizzi, Eileen Ryan, Werner Kaminsky, Didier Leroy, María Santos Martínez-Martínez, Maria Belen Jimenez-Diaz, Santiago Ferrer Bazaga, Iñigo Angulo-Barturen & 6 others David Waterson, Jeremy N Burrows, Dave Matthews, Susan A Charman, Margaret A Phillips, Pradipsinh K Rathod

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)5416-5431
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number11
DOIs
Publication statusPublished - 9 Jun 2016

Cite this

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. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 11. pp. 5416-5431.
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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.",
author = "Sreekanth Kokkonda and Xiaoyi Deng and White, {Karen L} and Coteron, {Jose M} and Maria Marco and {de las Heras}, Laura and John White and {El Mazouni}, Farah and Tomchick, {Diana R} and Krishne Manjalanagara and Rudra, {Kakali Rani} and Gong Chen and Julia Morizzi and Eileen Ryan and Werner Kaminsky and Didier Leroy and Mart{\'i}nez-Mart{\'i}nez, {Mar{\'i}a Santos} and Jimenez-Diaz, {Maria Belen} and Bazaga, {Santiago Ferrer} and I{\~n}igo Angulo-Barturen and David Waterson and Burrows, {Jeremy N} and Dave Matthews and Charman, {Susan A} and Phillips, {Margaret A} and Rathod, {Pradipsinh K}",
year = "2016",
month = "6",
day = "9",
doi = "10.1021/acs.jmedchem.6b00275",
language = "English",
volume = "59",
pages = "5416--5431",
journal = "Journal of Medicinal Chemistry",
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Kokkonda, S, Deng, X, White, KL, Coteron, JM, Marco, M, de las Heras, L, White, J, El Mazouni, F, Tomchick, DR, Manjalanagara, K, Rudra, KR, Chen, G, Morizzi, J, Ryan, E, Kaminsky, W, Leroy, D, Martínez-Martínez, MS, Jimenez-Diaz, MB, Bazaga, SF, Angulo-Barturen, I, Waterson, D, Burrows, JN, Matthews, D, Charman, SA, Phillips, MA & Rathod, PK 2016, 'Tetrahydro-2-naphthyl and 2-Indanyl triazolopyrimidines targeting Plasmodium falciparum Dihydroorotate Dehydrogenase display potent and selective antimalarial activity' Journal of Medicinal Chemistry, vol. 59, no. 11, pp. 5416-5431. https://doi.org/10.1021/acs.jmedchem.6b00275

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.

In: Journal of Medicinal Chemistry, Vol. 59, No. 11, 09.06.2016, p. 5416-5431.

Research output: Contribution to journalArticleResearchpeer-review

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

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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UR - http://pubs.acs.org.ezproxy.lib.monash.edu.au/doi/pdf/10.1021/acs.jmedchem.6b00275

U2 - 10.1021/acs.jmedchem.6b00275

DO - 10.1021/acs.jmedchem.6b00275

M3 - Article

VL - 59

SP - 5416

EP - 5431

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -