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Benzoxaborole antimalarial agents. Part 4. Discovery of potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.
Zhang, Yong-Kang; Plattner, Jacob J; Easom, Eric E; Jacobs, Robert T; Guo, Denghui; Sanders, Virginia; Freund, Yvonne R; Campo, Brice; Rosenthal, Philip J; Bu, Wei; Gamo, Francisco-Javier; Sanz, Laura M; Ge, Min; Li, Liang; Ding, Jie; Yang, Yin.
Affiliation
  • Zhang YK; †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • Plattner JJ; †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • Easom EE; †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • Jacobs RT; †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • Guo D; §Department of Medicine, University of California, San Francisco, Box 0811, San Francisco, California 94143, United States.
  • Sanders V; †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • Freund YR; †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • Campo B; ‡International Center Cointrin, Medicines for Malaria Venture, Block G, 20 route de Pré-Bois, POB 1826, CH-1215 Geneva, Switzerland.
  • Rosenthal PJ; §Department of Medicine, University of California, San Francisco, Box 0811, San Francisco, California 94143, United States.
  • Bu W; †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
  • Gamo FJ; ∥Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
  • Sanz LM; ∥Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
  • Ge M; ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
  • Li L; ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
  • Ding J; ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
  • Yang Y; ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
J Med Chem ; 58(13): 5344-54, 2015 Jul 09.
Article in En | MEDLINE | ID: mdl-26067904
ABSTRACT
A series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the changes in antimalarial activity which result from 6-aryloxy structural variation, substituent modification on the pyrazine ring, and optimization of the side chain ester group. This SAR study discovered highly potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 27-34) with IC50s = 0.2-22 nM against cultured Plasmodium falciparum W2 and 3D7 strains. Compound 9 also demonstrated excellent in vivo efficacy against P. berghei in infected mice (ED90 = 7.0 mg/kg).
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Plasmodium falciparum / Pyrazines / Boron Compounds / Microsomes, Liver / Malaria, Falciparum / Bridged Bicyclo Compounds, Heterocyclic / Antimalarials Limits: Animals / Female / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2015 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Plasmodium falciparum / Pyrazines / Boron Compounds / Microsomes, Liver / Malaria, Falciparum / Bridged Bicyclo Compounds, Heterocyclic / Antimalarials Limits: Animals / Female / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2015 Type: Article Affiliation country: United States