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Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity. 2003

Richard L Jarvest, and John M Berge, and Murray J Brown, and Pamela Brown, and John S Elder, and Andrew K Forrest, and C S V Houge-Frydrych, and Peter J O'Hanlon, and David J McNair, and Stephen Rittenhouse, and Robert J Sheppard
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. richard_l_jarvest@gsk.com

Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.

UI MeSH Term Description Entries
D008718 Methionine-tRNA Ligase An enzyme that activates methionine with its specific transfer RNA. EC 6.1.1.10. Methionyl T RNA Synthetase,Met-tRNA Ligase,Methionyl-tRNA Synthetase,Ligase, Met-tRNA,Ligase, Methionine-tRNA,Met tRNA Ligase,Methionine tRNA Ligase,Methionyl tRNA Synthetase,Synthetase, Methionyl-tRNA
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006094 Gram-Positive Bacteria Bacteria which retain the crystal violet stain when treated by Gram's method. Gram Positive Bacteria
D000890 Anti-Infective Agents Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection. Anti-Infective Agent,Anti-Microbial Agent,Antimicrobial Agent,Microbicide,Microbicides,Anti-Microbial Agents,Antiinfective Agents,Antimicrobial Agents,Agent, Anti-Infective,Agent, Anti-Microbial,Agent, Antimicrobial,Agents, Anti-Infective,Agents, Anti-Microbial,Agents, Antiinfective,Agents, Antimicrobial,Anti Infective Agent,Anti Infective Agents,Anti Microbial Agent,Anti Microbial Agents
D013210 Staphylococcus A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are found on the skin and mucous membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals.
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D016983 Enterococcus A genus of gram-positive, coccoid bacteria consisting of organisms causing variable hemolysis that are normal flora of the intestinal tract. Previously thought to be a member of the genus STREPTOCOCCUS, it is now recognized as a separate genus.
D020128 Inhibitory Concentration 50 The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture. IC50,Concentration 50, Inhibitory
D024881 Drug Resistance, Bacterial The ability of bacteria to resist or to become tolerant to chemotherapeutic agents, antimicrobial agents, or antibiotics. This resistance may be acquired through gene mutation or foreign DNA in transmissible plasmids (R FACTORS). Antibiotic Resistance, Bacterial,Antibacterial Drug Resistance

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