title: Novel Sulfamethoxazole Ureas and Oxalamide as Potential Antimycobacterial Agents.
abstract: Infections caused byMycobacterium tuberculosis(Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-basedn-alkyl ureas (C₁-C12), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity againstMtb.and three NTM strains (M. avium,M. kansasii). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 µM. The highest activity showed 4,4'-[carbonylbis(azanediyl)]bis[N-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2-62.5 µM (i.e., 1.07-33.28 µg/mL). Amongn-alkyl ureas, methyl group is optimal for the inhibition of bothMtb.and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values.
authors.affiliation: Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005 Hradec Králové, Czech Republic. martin.kratky@faf.cuni.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Krátký
authors.affiliation: Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské námĕstí 7, 70200 Ostrava, Czech Republic. Jirina.Stolarikova@zu.cz.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.affiliation: Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005 Hradec Králové, Czech Republic. vinsova@faf.cuni.cz.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Vinšová
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects*; D013420:Sulfamethoxazole / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D014508:Urea; D013420:Sulfamethoxazole
keywords: antimycobacterial activity; in vitro activity; oxalamide; sulfamethoxazole; sulfonamides; tuberculosis; ureas