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基于结构的设计,的优化,合成和对Trypanosoma cruzi活跃化合物的生物评估

Gleybson Correia de Almeida¹, Gerliny Bezerra de Oliveira¹, Zenaide da Silva Monte¹

¹Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Federal University of Pernambuco/UFPE, Recife, Brazil.

Chemical biology & drug design

|July 16, 2023

概括

新的皮里米丁化合物通过抑制Trypanosoma cruzi.中的cruzipain酶来治疗查加斯病. 最有效的化合物5e显示出强大的三酸性活性和对哺乳动物细胞的低毒性.

科学领域:

药用化学医学化学
寄生虫学的寄生虫学
计算化学的计算化学

背景情况:

查加斯病是由Trypanosoma cruzi引起的,在全球范围内影响着数百万人,主要是贫困人口.
目前对查加斯病的治疗方法缺乏足够的疗效和安全性.
克鲁西是一种T. cruzi酶,是药物开发的关键治疗标.

研究的目的:

设计和合成具有增强的三酸活性和选择性的新型胺类同类物.
通过分子对接和ADMET预测优化胺化合物ZN3F的活性.
为了识别用于查加斯病治疗的强效克鲁兹胺抑制剂.

主要方法:

分子对接和in silico ADMET属性预测被用于化合物设计.
合成了八种4 - 氨基-5 - 碳二烯胺类类似物.
对T. cruzi的图拉胡恩菌株进行了体外测试,并对L929细胞进行了细胞毒性测试.

主要成果:

设计的类似物与克鲁西活性部位的关键氨基酸残留物具有有利的结合相互作用.
所有合成的衍生品都表现出对T. cruzi的抑制活性.
化合物5e成为一种高度强效和选择性抑制剂 (IC50 = 2.79 μM,SI = 31.3),对哺乳动物细胞的毒性降低.

结论:

该研究验证了基于结构的药物设计方法,用于开发有效的查加斯病治疗方法.
皮里米丁衍生物显示出作为三毒剂的显著潜力.
这项研究为克鲁西潘抑制提供了宝贵的分子洞察力.

关键词:

这种植物是Trypanosoma cruzi.克鲁兹帕因 (Cruzipain) 在西班牙.的化合物的化合物分子对接的分子对接.皮里米丁酸盐是一种胺酸.基于结构的基于结构的.

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