Design, synthesis and antimycobacterial activities of 1-methyl-2-alkenyl-4(1H)-quinolones

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 1; pp. 567 - 579
• Main Authors: Wube, Abraham A., Hüfner, Antje, Thomaschitz, Christina, Blunder, Martina, Kollroser, Manfred, Bauer, Rudolf, Bucar, Franz
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2011; Elsevier Science
• Subjects: 1-Methyl-2-alkenyl-4(1H)-quinolone; alkaloids; antibacterial properties; Antimycobacterial; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Cell Line; cytotoxicity; diploidy; Drug Screening Assays, Antitumor; fast growing strains; growth retardation; Humans; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Mycobacterium; Mycobacterium fortuitum; quinolones; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; SAR; structure-activity relationships; Tuberculosis; 1-Methyl-2-alkenyl-4(1H)-quinolone; Tuberculosis; SAR; Antimycobacterial
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.10.060

A series of new 1-methyl-2-alkenyl-4(1H)-quinolones lacking carboxyl, fluorine and piperazinyl at position-3, -6 and -7, respectively, have been synthesized and tested in vitro against fast growing species of mycobacteria. A series of 23 new 1-methyl-2-alkenyl-4(1H)quinolones have been synthesized and evaluated in vitro for their antimycobacterial activities against fast growing species of mycobacteria, such as Mycobacterium fortuitum, M. smegmatis and M. phlei. The compounds displayed good to excellent inhibition of the growth of the mycobacterial test strains with improved antimycobacterial activity compared to the hit compound, evocarpine. The most active compounds, which possessed chain length of 11–13 carbons at position-2 displayed potent inhibitory effects with an MIC value of 1.0mg/L. In a human diploid embryonic lung cell line, MRC-5 cytotoxicity assay, the alkaloids showed weak to moderate cytotoxic activity. Biological evaluation of these evocarpine analogues on the less pathogenic fast growing strains of mycobacteria showed an interesting antimycobacterial profile and provided significant insight into the structure–activity relationships.