title: Synthesis and biological activity of alkynoic acids derivatives against mycobacteria.
abstract: 2-Alkynoic acids have bactericidal activity against Mycobacterium smegmatis but their activity fall sharply as the length of the carbon chain increased. In this study, derivatives of 2-alkynoic acids were synthesized and tested against fast- and slow-growing mycobacteria. Their activity was first evaluated in M. smegmatis against their parental 2-alkynoic acids, as well as isoniazid, a first-line antituberculosis drug. The introduction of additional unsaturation or heteroatoms into the carbon chain enhanced the antimycobacterial activity of longer chain alkynoic acids (more than 19 carbons long). In contrast, although the modification of the carboxylic group did not improve the antimycobacterial activity, it significantly reduced the toxicity of the compounds against eukaryotic cells. Importantly, 4-(alkylthio)but-2-ynoic acids, had better bactericidal activity than the parental 2-alkynoic acids and on a par with isoniazid against the slow-grower Mycobacterium bovis BCG. These compounds had also low toxicity against eukaryotic cells, suggesting that they could be potential therapeutic agents against other types of topical mycobacterial infections causing skin diseases including Mycobacterium abscessus, Mycobacterium ulcerans, and Mycobacterium leprae. Moreover, they provide a possible scaffold for future drug development.
authors.affiliation: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, United States; Department of Chemistry and Biochemistry, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilchèze
authors.affiliation: Gray Box Biology LLC, 423 West 127th Street, New York, NY 10027, United States.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Leung
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.affiliation: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, United States. Electronic address: jacobsw@hhmi.org.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D005231:Fatty Acids, Unsaturated
keywords: Alkynoic; Antimycobacterial; InhA; Sulfur