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

Journal of Medicinal Chemistry

Volumn 59, Issue 11, 2016, Pages 5416-5431

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

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF TEXAS AT DALLAS   (United States)

^c MONASH UNIVERSITY   (Australia)

^d GSK   (Spain)

^e SYNGENE INTERNATIONAL LTD   (India)

^f Medicines for Malaria Venture   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

2 (1,1 DIFLUOROETHYL) 5 METHYL N (1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) 5 METHYL N [5 (METHYLSULFONYL) 2,3 DIHYDRO 1H INDEN 2 YL] [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (2,3 DIHYDRO 1H INDEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (4 FLUORO 2,3 DIHYDRO 1H INDEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (6 BROMO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (6 CHLORO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (6 FLUORO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (6 FLUORO 7 (TRIFLUOROMETHYL) 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (6 METHOXY 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (6,7 DIFLUORO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (7 BROMO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (7 FLUORO 6 (TRIFLUOROMETHYL) 1,2,3,4-TETRAHYDRO NAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 (1,1 DIFLUOROETHYL) N (7 METHOXY 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; 2 [2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 YLAMINO] N,N DIMETHYL 2,3 DIHYDRO 1H INDENE 5 SULFONAMIDE; 5 METHYL N (1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) N (TRIFLUOROMETHYL) [ 1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; ANTIMALARIAL AGENT; DIHYDROOROTATE DEHYDROGENASE; N (4,7 DIFLUORO 2,3 DIHYDRO 1H INDEN 2 YL) 2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (4,7 DIMETHYL 2,3 DIHYDRO 1H INDEN 2 YL) 2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (5 BROMO 2,3 DIHYDRO 1H INDEN 2 YL) 2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (5 CHLORO 2,3 DIHYDRO 1H INDEN 2 YL) 2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (5,6 DICHLORO 2,3 DIHYDRO 1H INDEN 2 YL) 2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (5,6 DIFLUORO 2,3 DIHYDRO 1H INDEN 2 YL) 2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (6 FLUORO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL 2 (TRIFLUOROMETHYL) [ 1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (7 CHLORO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 2 (1,1 DIFLUOROETHYL) 5 METHYL [1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; N (7 CHLORO 1,2,3,4 TETRAHYDRONAPHTHALEN 2 YL) 5 METHYL 2 (TRIFLUOROMETHYL) [ 1,2,4]TRIAZOLO[1,5 A]PYRIMIDIN 7 AMINE; NAPHTHALENE DERIVATIVE; PYRIMIDINE DERIVATIVE; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ENZYME INHIBITOR; OXIDOREDUCTASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIMALARIAL ACTIVITY; ARTICLE; CONTROLLED STUDY; CRYSTALLIZATION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG TOLERABILITY; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; INTRINSIC CLEARANCE; LIMIT OF QUANTITATION; LIVER MICROSOME; MALARIA; MAXIMUM PLASMA CONCENTRATION; METABOLIC CLEARANCE; METABOLIC STABILITY; MODEL; MOUSE; MOUSE MODEL; NONHUMAN; PHASE 2 CLINICAL TRIAL; PHYSICAL CHEMISTRY; PLASMA PROTEIN BINDING; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PROTEIN TARGETING; QT PROLONGATION; RAT; SCID MOUSE; STEADY STATE; TIME TO MAXIMUM PLASMA CONCENTRATION; VOLUME OF DISTRIBUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DISEASE MODEL; DOSE RESPONSE; DRUG EFFECTS; DRUG SENSITIVITY; ENZYMOLOGY; MALARIA, FALCIPARUM; METABOLISM; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ANIMALS; ANTIMALARIALS; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; ENZYME INHIBITORS; HUMANS; MALARIA, FALCIPARUM; MICE; MICE, SCID; MOLECULAR STRUCTURE; OXIDOREDUCTASES ACTING ON CH-CH GROUP DONORS; PARASITIC SENSITIVITY TESTS; PLASMODIUM FALCIPARUM; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

EID: 84974560565     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00275     Document Type: Article

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