吡唑并[1,5-c]嘧啶类抗利什曼原虫化合物的合成、建模及生物评价。
Synthesis, modeling and biological evaluation of hybrids from pyrazolo[1,5c]pyrimidine as antileishmanial agents.
机构信息
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr ElSheikh 33516, Egypt.
出版信息
Future Med Chem. 2017 Oct;9(16):1913-1929. doi: 10.4155/fmc-2017-0120. Epub 2017 Oct 13.
AIM
A new series of pyrazolo[1,5-c]pyrimidines were synthesized by different hybridization strategies.
METHODOLOGY
All structures were confirmed by IR, H, C, H-C heteronuclear multiple-quantum correlation (HMQC) spectra and microanalysis. They were evaluated for their in vitro antileishmanial activity against miltefosine and amphotericin B deoxycholate as reference drugs.
RESULTS
The most active compounds 2a and 9a demonstrated superior potencies to miltefosine by ten- and six-fold, respectively, for the promastigote form, and by 5.5-fold for the amastigote form. Their binding scenario to Leishmania major pteridine reductase was rationalized by docking experiments. In addition, all compounds were safe for the experimental animals orally up to 150 mg/kg and parenterally up to 75 mg/kg.
CONCLUSION
This study provides novel chemotype class for antileishmanial activity. [Formula: see text].
目的
通过不同的杂化策略合成了一系列新型吡唑并[1,5-c]嘧啶。
方法
所有结构均通过 IR、H、C、H-C 异核多量子相关 (HMQC) 谱和微量分析得到证实。以米替福新和两性霉素 B 脱氧胆酸盐作为参考药物，评估它们对体外抗利什曼原虫的活性。
结果
最活跃的化合物 2a 和 9a 在无鞭毛体形式下分别比米替福新高出十倍和六倍，在无鞭毛体形式下高出五倍半。通过对接实验，合理推断了它们与利什曼原虫蝶呤还原酶的结合情况。此外，所有化合物经口给药高达 150mg/kg 和经皮给药高达 75mg/kg 时对实验动物均安全。
结论
本研究为抗利什曼原虫活性提供了新的化学类型。[化学式：见正文]。
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