Abstract
Infections caused by Mycobacterium 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-based n-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 against Mtb. 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). Among n-alkyl ureas, methyl group is optimal for the inhibition of both Mtb. 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.
Highlights
The progression of resistance to clinically used drugs among human pathogenic bacteria justifies the development of new antimicrobial agents effective against, e.g., Mycobacterium tuberculosis (Mtb.) nontuberculous mycobacteria (NTM), methicillin-resistant Staphylococcus aureus, and polyresistant Gram-negative species [1].The modification of known drugs represents an established and effective approach in drug design.Sulfonamides have been widely used for the treatment of bacterial and protozoan infections
Longer alkyls led to increased minimum inhibitory concentration (MIC) values, heptyl being an exception for nontuberculous (atypical) mycobacteria (NTM)
E.g., Ameen and Drancourt [3,4] demonstrated that mycobacterial strains (Mtb., Mycobacterium avium complex) are susceptible to clinically-achievable concentrations of sulfonamides and the investigation of sulfonamide derivatives as potential antimycobacterial agents has been initiated [1,5]
Summary
The progression of resistance to clinically used drugs among human pathogenic bacteria justifies the development of new antimicrobial agents effective against, e.g., Mycobacterium tuberculosis (Mtb.) nontuberculous (atypical) mycobacteria (NTM), methicillin-resistant Staphylococcus aureus, and polyresistant Gram-negative species [1].The modification of known drugs represents an established and effective approach in drug design.Sulfonamides have been widely used for the treatment of bacterial and protozoan infections. The progression of resistance to clinically used drugs among human pathogenic bacteria justifies the development of new antimicrobial agents effective against, e.g., Mycobacterium tuberculosis (Mtb.) nontuberculous (atypical) mycobacteria (NTM), methicillin-resistant Staphylococcus aureus, and polyresistant Gram-negative species [1]. The modification of known drugs represents an established and effective approach in drug design. E.g., Ameen and Drancourt [3,4] demonstrated that mycobacterial strains (Mtb., Mycobacterium avium complex) are susceptible to clinically-achievable concentrations of sulfonamides (sulfadiazine, sulfamethoxazole, including its combination with trimethoprim) and the investigation of sulfonamide derivatives as potential antimycobacterial agents has been initiated [1,5]. Sulfonamides are well-known inhibitors of dihydropteroate synthases involved in the folate pathway [6], β-carbonic anhydrases [7,8], acetohydroxyacid synthase [9] or β-ketoacyl synthases [10]
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