New antifolate inhibitors for Mycobacterium avium.
New antifolate inhibitors for Mycobacterium avium.
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DOI：
10.2174/157340606778250225
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发表时间：
2006-09-01
期刊：
影响因子：
--
通讯作者：
Barrow, W W
中科院分区：
文献类型：
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作者：
Barrow, E W;Suling, W J;Barrow, W W
本研究扩展了我们以前关于鸟分枝杆菌二氢叶酸还原酶（DHFR）的新抗叶酸剂的工作。本研究的目的是合成和测试2，4-二氨基-5-甲基-5-脱氮杂吡啶类的一般类别中的新衍生物，以努力改善对MAC DHFR的溶解度和选择性，同时保持对人DHFR缺乏选择性。如前所述合成新的6-[2 '，5'-二烷氧基苯基）甲基]-取代的DMDP类似物。3株MAC（NJ 211、NJ 3404和NJ 168）和M.结核分枝杆菌H37 Ra（MTB）用于评价新衍生物。使用先前描述的比色（alamarBlue（R））微量稀释肉汤测定法来确定最小抑制浓度（MIC）。在经验证的酶试验中使用纯化重组人（rDHFR）、MAC rDHFR和MTB rDHFR，以获得IC（50）值并测定衍生物的选择性比（SR）。对于MAC菌株，MIC范围为< 0.25 to >16 μ g/mL。对MAC最具活性的衍生物是SRI-20920，其对三种菌株的MIC分别为0.25、0.25和8 μ g/mL。最具选择性的衍生物是SRI-20730，MAC rDHFR和hDHFR的IC（50 s）分别为29和67，781 nM，SR为2，337。MTB的MIC范围为4至>64微克/毫升，SR范围通常为0.32至2.5。这些结果进一步证实了这组DMDP衍生物对MAC的选择性活性的效用。
The present study extends our previous work regarding new antifolates for Mycobacterium avium (MAC) dihydrofolate reductase (DHFR). The objectives of this study were to synthesize and test new derivatives in the general class of 2,4-diamino-5-methyl-5-deazapteridines in an effort to improve solubility and selectivity for the MAC DHFR, while maintaining lack of selectivity for the human DHFR. New 6-[2', 5'-dialkoxyphenyl) methyl]-substituted DMDP analogs were synthesized as previously described. Three clinical isolates of MAC (NJ211, NJ3404, and NJ168) and M. tuberculosis H37Ra (MTB) were used to evaluate the new derivatives. A previously described colorimetric (alamarBlue(R)) microdilution broth assay was used to determine minimal inhibitory concentrations (MIC). Purified recombinant human (rDHFR), MAC rDHFR, and MTB rDHFR were used in a validated enzyme assay to obtain IC(50) values and to determine selectivity ratios (SR) for the derivatives. For the MAC strains, the MICs ranged from < 0.25 to > 16 microg/mL. The most active derivative against MAC was SRI-20920 which had MICs of 0.25, 0.25, and 8 microg/mL for the three strains, respectively. The most selective derivative was SRI-20730 with IC(50s) of 29 and 67,781 nM for MAC rDHFR and hDHFR, respectively, and a SR of 2,337. MICs for MTB ranged from 4 to >64 microg/mL and the SR, in general, ranged from 0.32 to 2.5. These results further substantiate the utility of this group of DMDP derivatives for selective activity against MAC.