title: Synthesis of N-substituted 2-[(1E)-alkenyl]-4-(1H)-quinolone derivatives as antimycobacterial agents against non-tubercular mycobacteria.
abstract: In an effort to improve biological activities and to examine antimycobacterial-lipophilicity relationships of 2-[(1E)-alkenyl)]-4-(1H)-quinolones, we have synthesized a series of 30 quinolones by introducing several alkyl groups, an alkenyl and an alkynyl group at N-1. All synthetic compounds were first tested in vitro against Mycobacterium smegmatis and the most active compounds (MIC values ∼3.0-7.0 μM) were further examined against three other rapidly growing strains of mycobacteria using a microtiter broth dilution assay. The Clog P values of the synthetic compounds were calculated to provide an estimate of their lipophilicity. Compounds 18e, 19a and 19b displayed the most potent inhibitory effect against M. smegmatis mc(2)155 with an MIC value of ∼1.5 μM, which was twenty fold and thirteen fold more potent than isoniazid and ethambutol, respectively. On the other hand, compounds 17e, 18e and 19a were most active against Mycobacterium fortuitum and Mycobacterium phlei with an MIC value of ∼3.0 μM. In the human diploid embryonic lung cell line MRC-5 cytotoxicity assay, the derivatives showed moderate to strong cytotoxic activity. Although the antimycobacterial activity of our synthetic compounds could not be correlated with the calculated log P values, an increase in lipophilicity enhances the antimycobacterial activity and C13-C15 total chain length at positions 1 and 2 is required to achieve optimal inhibitory effect against the test strains.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl Franzens Universität Graz, Universitätsplatz 4, A-8010 Graz, Austria.
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Wube
authors.forename: Franz
authors.initials: F
authors.lastname: Bucar
authors.forename: Christina
authors.initials: C
authors.lastname: Hochfellner
authors.forename: Martina
authors.initials: M
authors.lastname: Blunder
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bauer
authors.forename: Antje
authors.initials: A
authors.lastname: Hüfner
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D015363:Quinolones