title: Benzimidazole analogs as WTA biosynthesis inhibitors targeting methicillin resistant Staphylococcus aureus.
abstract: A series of benzimidazole analogs have been synthesized to improve the profile of the previous lead compounds tarocin B and 1. The syntheses, structure-activity relationships, and selected biochemical data of these analogs are described. The optimization efforts allowed the identification of 21, a fluoro-substituted benzimidazole, exhibiting potent TarO inhibitory activity and typical profile for a wall teichoic acid (WTA) biosynthesis inhibitor. Compound 21 displayed a potent synergistic and bactericidal effect in combination with imipenem against diverse methicillin-resistant Staphylococci.
authors: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States. Electronic address: shu-wei.yang@merck.com.
authors: Shu-Wei
authors: SW
authors: Yang
authors: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Jianping
authors: J
authors: Pan
authors: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Christine
authors: C
authors: Yang
authors: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Marc
authors: M
authors: Labroli
authors: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Weidong
authors: W
authors: Pan
authors: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: John
authors: J
authors: Caldwell
authors: Structure Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Sookhee
authors: S
authors: Ha
authors: In Vitro Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Sandra
authors: S
authors: Koseoglu
authors: In Vitro Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Jing C
authors: JC
authors: Xiao
authors: In Vitro Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Todd
authors: T
authors: Mayhood
authors: In Vitro Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Payal R
authors: PR
authors: Sheth
authors: In Vitro Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Charles G
authors: CG
authors: Garlisi
authors: Pharmacokinetics PPDM, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Jin
authors: J
authors: Wu
authors: Infectious Disease, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Sang Ho
authors: SH
authors: Lee
authors: Infectious Disease, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Hao
authors: H
authors: Wang
authors: Infectious Disease, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Christopher M
authors: CM
authors: Tan
authors: Infectious Disease, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Terry
authors: T
authors: Roemer
authors: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors: Jing
authors: J
authors: Su
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D051381:Rats; D013329:Structure-Activity Relationship; D013682:Teichoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D013682:Teichoic Acids
keywords: Antibacterial; MRSA; WTA; Wall teichoic acid