Synthesis and biological evaluation of pyrazolopyrimidines as potential antibacterial agents.
Synthesis and biological evaluation of pyrazolopyrimidines as potential antibacterial agents.
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DOI：
10.1016/j.bmcl.2015.10.096
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发表时间：
2015-12-15
影响因子：
2.7
通讯作者：
Hagen TJ
中科院分区：
文献类型：
--
作者：
Goshu GM;Ghose D;Bain JM;Pierce PG;Begley DW;Hewitt SN;Udell HS;Myler PJ;Meganathan R;Hagen TJ
发现片段F0 L7185（化合物17）是针对从细菌分离的IspD和IspE酶的命中物，并且合成了一系列含有吡唑并嘧啶核心的类似物。在Kirby-Bauer纸片扩散药敏试验中，这些化合物中的大多数抑制了泰国伯克霍尔德氏菌（Bt）和铜绿假单胞菌（Pa）的生长。化合物29在0.1 mM（32.2 μg/mL）下显示出抑制活性，其与对照化合物卡那霉素（48.5 μg/mL）相当。化合物29在0.5mM下也显示出对卡那霉素抗性铜绿假单胞菌的抑制活性。饱和转移差NMR（STD-NMR）筛选这些化合物对BtIspD和BtIspE表明，这些化合物中的大多数显着与BtIspE相互作用，这表明该化合物可能通过破坏类异戊二烯生物合成抑制Bt的生长。用BtIspE对化合物29进行配体表位作图表明，2，4-二氯苯基上的氢比吡唑并嘧啶环上的氢更接近酶表面。
The fragment FOL7185 (compound 17) was found to be a hit against IspD and IspE enzymes isolated from bacteria, and a series of analogs containing the pyrazolopyrimidine core were synthesized. The majority of these compounds inhibited the growth of Burkholderia thailandensis (Bt) and Pseudomonas aeruginosa (Pa) in the Kirby-Bauer disk diffusion susceptibility test. Compound 29 shows inhibitory activity at 0.1 mM (32.2 µg/mL), which is comparable to the control compound kanamycin (48.5 µg/mL). Compound 29 also shows inhibitory activity at 0.5 mM against kanamycin resistant P. aeruginosa. Saturation transfer difference NMR (STD-NMR) screening of these compounds against BtIspD and BtIspE indicated that most of these compounds significantly interact with BtIspE, suggesting that the compounds may inhibit the growth of Bt by disrupting isoprenoid biosynthesis. Ligand epitope mapping of compound 29 with BtIspE indicated that hydrogens on 2,4-dichlorophenyl group have higher proximity to the surface of the enzyme than hydrogens on the pyrazolopyrimidine ring.