Antimycobacterial Activities of 2,4-Diamino-5-Deazapteridine Derivatives and Effects on Mycobacterial Dihydrofolate Reductase

摘要: Development of new antimycobacterial agents for Mycobacterium avium complex (MAC) infections is important particularly persons coinfected with human immunodeficiency virus. The objectives this study were to evaluate the in vitro activity 2,4-diamino-5-methyl-5-deazapteridines (DMDPs) against MAC and assess their activities dihydrofolate reductase recombinant enzyme (rDHFR). Seventy-seven DMDP derivatives evaluated initially one three strains (NJ168, NJ211, and/or NJ3404). MICs determined 10-fold dilutions drug a colorimetric (Alamar Blue) microdilution broth assay. rDHFR 50% inhibitory concentrations versus those also determined. Substitutions at position 5 pteridine moiety included -CH 3 , 2 CH OCH groups. Additionally, different substituted unsubstituted aryl groups linked 6 through two-atom bridge either NH, N(CH ), or S. All but 4 77 active NJ168 ≤13 μg/ml. Depending on strain used, 81 87% had ≤1.3 Twenty-one >100-fold more than rDHFR. In general, selectivity was dependent composition attached group substitutions 2′ 5′ positions phenyl ring. Using assessment, rational synthetic approach implemented that resulted derivative significant intracellular MAC-infected Mono Mac monocytic cell line. These results demonstrate it possible synthesize have selective MAC.