Synthesis of quinoxaline compounds and their medicinal properties against mycobacterium tuberculosis

Abstract

In an attempt to synthesise quinoxaline-ferrocene compounds with antimycobacterial activity; a series of quinoxaline alkynyl derivatives were successfully synthesised from 3- (quinoxalin-3-yl)prop-2-yn-1-ol 86A and 3-(6-chloroquinoxalin-2-yl)prop-2-yn-1-ol 86B. In this series compounds 87A – B, 90A – B, and 93A – C were intermediates obtained in an effort to synthesise quinoxaline-ferrocene compounds. Treatment of either 86A or 86B with various acid chlorides afforded quinoxaline alkynyl ester derivatives 97A - 97B. Within this series, two quinoxaline-ferrocene compounds 3-(quinoxalin-3-yl)prop-2-ynyl ferrocetate 97A-iv and 3-(6-chloroquinoxalin-2-yl)prop-2-ynyl ferrocetate 97B-iv were successfully incorporated with ferrocenoyl chloride and obtained in 42 - 43% yield. The reactions of 3-chloroquinoxaline-2-carbonyl chloride 99 with ferrocenyl alcohol and ferrocenyl amine were unsuccessful. However, 3-chloroquinoxaline-2-carbonyl ester 100A - C and amide 101A - D derivatives with various alcohols and amines were obtained. The structures of all the compounds were confirmed by spectroscopic analysis (NMR, FT-IR and HRMS). The synthesised compounds were all evaluated for preliminary in-vitro antimycobacterial activity. The results obtained exhibited compound 90B with the highest activity against Mtb H37RV strain at MIC90 of 1.13 µM, followed by 90A and 87A exhibiting MIC90 of 4.55 and 6.47 µM, respectively. The quinoxaline alkynyl ester derivatives were found to exhibit poor to good activity. Within this series, three compounds were found to exhibit antimycobacterial activity at MIC90 ˂ 20 µM with compound 97A-ii showing the highest activity at MIC90 of 16.18 µM, followed by 97A-i and 97B-iii showing MIC90 of 18.05 and 19.36 µM, respectively. From the two quixonaline-ferrocene compounds, compound 97A iv was found to exhibit antimycobacterial activity at MIC90 of 39.90 µM. However, compound 97B-iv was found to be inactive. The 3-chloroquinoxaline-2-carbonyl ester 100A - C and amide 101A - D derivatives were found to be inactive. However, compound 99-C was found to exhibit antimycobacterial activity at MIC90 of 40.66 µM. Compounds 86A, 86C, 87A and 90A were evaluated for in-vitro antiproliferative activity against cancer cell lines. The results of antiproliferative activity showed that compounds 86A and 87A exhibited excellent activity against A549 lung cancer cell lines. Compound 87A was found to be the most active against A549 cell line showing 50% viability-inhibition at 25 µM