Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure-Activity Relationships and Mechanism of Action.
Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure-Activity Relationships and Mechanism of Action.
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DOI：
10.1021/acsomega.2c05071
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发表时间：
2022-10-25
期刊：
影响因子：
4.1
通讯作者：
O'Reilly, Matthew C.
中科院分区：
文献类型：
--
作者：
Boyer, Zachary W.;Kessler, Hannah;Brosman, Hannah;Ruud, Kirsten J.;Falkowski, Alan F.;Viollet, Constance;Bourne, Christina R.;O'Reilly, Matthew C.
细菌对抗生素的耐药性给公共卫生带来了巨大的压力。发现通过独特机制起作用的新抗生素是对抗这种耐药性威胁的一个重要支柱。据报道，一种功能化的氨基二氢嘧啶通过抑制二氢叶酸还原酶（一种未开发的抗菌靶标）而表现出抗菌活性。尽管前景光明，但对其构效关系（SAR）和作用机制知之甚少。为了实现这一目标，我们对aza-Biginelli反应进行了优化，以制备功能化氨基二氢吡啶的集中文库，这在某些情况下需要使用变温核磁共振分析来确定化合物的身份和纯度。使用微量稀释法检测抗菌活性，并使用抗菌协同作用研究以及体外酶动力学、差示扫描荧光法和蛋白质晶体学评估化合物与二氢叶酸还原酶的相互作用。结果表明，该化合物类具有明显的抗菌SAR趋势（MIC值从bb0 64 ~ 4 μg/mL），具有广阔的抗菌开发前景。尽管如此，体外生化和生物物理研究与协同作用试验一起进行，对抗菌机制提出了质疑，表明需要进一步的研究来充分评估这类化合物的抗菌潜力。
Antibiotic resistance among bacteria puts immense strain on public health. The discovery of new antibiotics that work through unique mechanisms is one important pillar toward combating this threat of resistance. A functionalized amino dihydropyrimidine was reported to exhibit antibacterial activity via the inhibition of dihydrofolate reductase, an underexploited antibacterial target. Despite this promise, little is known about its structure–activity relationships (SAR) and mechanism of activity. Toward this goal, the aza-Biginelli reaction was optimized to allow for the preparation of focused libraries of functionalized amino dihydropyridines, which in some cases required the use of variable temperature NMR analysis for the conclusive assignment of compound identity and purity. Antibacterial activity was examined using microdilution assays, and compound interactions with dihydrofolate reductase were assessed using antimicrobial synergy studies alongside in vitro enzyme kinetics, differential scanning fluorimetry, and protein crystallography. Clear antibacterial SAR trends were unveiled (MIC values from >64 to 4 μg/mL), indicating that this compound class has promise for future development as an antibacterial agent. Despite this, the in vitro biochemical and biophysical studies performed alongside the synergy assays call the antibacterial mechanism into question, indicating that further studies will be required to fully evaluate the antibacterial potential of this compound class.
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