Synthesis of New Quinoxaline-2-carboxylate 1,4-Dioxide Derivatives as Anti-Mycobacterium tuberculosis Agents

• Published in: Journal of medicinal chemistry 2005-03, Vol.48 (6), p.2019-2025
• Main Authors: JASO, Andrés, ZARRANZ, Belén, ALDANA, Ignacio, MONGE, Antonio
• Format: Article
• Language: English
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biological and medical sciences; Cercopithecus aethiops; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Cyclic N-Oxides - chemical synthesis; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - pharmacology; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Medical sciences; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Pharmacology. Drug treatments; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Spectrophotometry, Infrared; Structure-Activity Relationship; Vero Cells
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049952w

Twenty-nine new 6(7)-substituted quinoxaline-2-carboxylate 1,4-dioxide derivatives were synthesized and evaluated for in vitro antituberculosis activity. In general, the in vitro activity is significantly affected by substituents on the quinoxaline nucleus. It has been observed that the presence of a chloro, methyl, or methoxy group in position 7 of the benzene moiety reduces the MIC and IC(50) values. However, antituberculosis activity principally depends on the substituents in the carboxylate group, improving in the following order: benzyl > ethyl > 2-methoxyethyl > allyl > tert-butyl. Fourteen compounds have been selected for macrophage assay, and the results show that ethyl and benzyl 3-methylquinoxaline-2-carboxylate 1,4-dioxide derivatives with the chlorine group in position 7 of the benzene moiety (compounds 10 and 26) and the unsubstituted derivatives (compounds 11 and 27) have good antitubercular activity, including activity in macrophages. In addition, compounds 7 and 28 (the only ones tested up to now) are active against drug-resistant strains of M. tuberculosis H(37)Rv. In conclusion, the potency, selectivity, and low cytotoxicity of these compounds make them valid leads for synthesizing new compounds that possess better activity.