Suling W J, Reynolds R C, Barrow E W, Wilson L N, Piper J R, Barrow W W
Southern Research Institute, Birmingham, AL 35205, USA.
J Antimicrob Chemother. 1998 Dec;42(6):811-5. doi: 10.1093/jac/42.6.811.
Twelve lipophilic 2,4-diamino-5-methyl-5-deazapteridine derivatives and trimethoprim were evaluated for activity against Mycobacterium tuberculosis and Mycobacterium avium in vitro. Six of the compounds had MICs of < or =12.8 mg/L and < or =1.28 mg/L against M. tuberculosis and M. avium, respectively; trimethoprim MICs were >128 mg/L and >12.8 but < or =128 mg/L, respectively. Two compounds, with either a 2-methyl-5-methoxy phenyl or 2-methoxy-5-trifluoromethyl phenyl linked at the 6-position of the deazapteridine moiety by a CH2NH bridge, had MICs of < or =0.13 mg/L against M. avium; the two compounds also had apparent I50 values for dihydrofolate reductase of 2 and 8 nM, respectively, compared with an I50 of 400 nM with trimethoprim. Four of the compounds were selectively toxic to mycobacteria as compared with Vero cells. These results demonstrated that lipophilic antifolates can be synthesized which are more active against mycobacteria than trimethoprim and which possess selective toxicity.
对12种亲脂性2,4 -二氨基-5 -甲基-5 -去氮蝶啶衍生物和甲氧苄啶进行了体外抗结核分枝杆菌和鸟分枝杆菌活性评估。其中6种化合物对结核分枝杆菌和鸟分枝杆菌的最低抑菌浓度（MIC）分别≤12.8 mg/L和≤1.28 mg/L；甲氧苄啶的MIC分别>128 mg/L和>12.8但≤128 mg/L。两种化合物，其在去氮蝶啶部分的6位通过CH2NH桥连接有2 -甲基-5 -甲氧基苯基或2 -甲氧基-5 -三氟甲基苯基，对鸟分枝杆菌的MIC≤0.13 mg/L；与甲氧苄啶的半数抑制浓度（I50）为400 nM相比，这两种化合物对二氢叶酸还原酶的表观I50值分别为2 nM和8 nM。与Vero细胞相比，其中4种化合物对分枝杆菌具有选择性毒性。这些结果表明，可以合成出比甲氧苄啶对分枝杆菌更具活性且具有选择性毒性的亲脂性抗叶酸剂。
