title: Benzoxaborole antimalarial agents. Part 4. Discovery of potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.
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).
authors.affiliation: †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.affiliation: †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
authors.affiliation: †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Easom
authors.affiliation: †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jacobs
authors.affiliation: §Department of Medicine, University of California, San Francisco, Box 0811, San Francisco, California 94143, United States.
authors.forename: Denghui
authors.initials: D
authors.lastname: Guo
authors.affiliation: †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
authors.forename: Virginia
authors.initials: V
authors.lastname: Sanders
authors.affiliation: †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
authors.forename: Yvonne R
authors.initials: YR
authors.lastname: Freund
authors.affiliation: ‡International Center Cointrin, Medicines for Malaria Venture, Block G, 20 route de Pré-Bois, POB 1826, CH-1215 Geneva, Switzerland.
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.affiliation: §Department of Medicine, University of California, San Francisco, Box 0811, San Francisco, California 94143, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: †Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Bu
authors.affiliation: ∥Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: ∥Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ge
authors.affiliation: ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.affiliation: ⊥Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011719:Pyrazines