基于Pyrazolo的ZIKV抑制剂[3,4-d]pyridazine-7-one核心:理性设计,体外评估和理论研究
Quang De Tran1,2, Cuong Quoc Nguyen1,2, Quang Le Dang3,4
1Department of Chemistry, College of Natural Sciences, Can Tho University, Can Tho 94000, Vietnam.
ACS omega
|January 1, 2024
概括
研究人员确定了新型化合物来对抗寨卡病毒 (ZIKV) 感染. 化合物9b表现出强大的抗ZIKV活性,并向病毒.
科学领域:
- 病毒学 病毒学
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
背景情况:
- 寨卡病毒 (ZIKV) 是一个重要的公共卫生问题,与严重的出生缺陷有关.
- 目前,没有批准的抗病毒药物用于治疗ZIKV感染.
- 开发有效的ZIKV疗法是一个关键的未满足的医疗需求.
研究的目的:
- 为了合成和评估新的pyrazolo[3,4-d]pyridazine-7-one衍生物作为潜在的抗ZIKV药物.
- 确定具有显著ZIKV抑制和有利的安全概况的化合物.
- 调查有前途的候选人对ZIKV的作用机制.
主要方法:
- 合成了16种pyrazolo[3,4-d]pyridazine-7-one衍生物的合成.
- 基于细胞的表型查以评估ZIKV感染的抑制.
- 盐水杀伤性生物测试用于初步的毒性评估.
- 分子对接和模拟以探索与ZIKV NS2B-NS3蛋白酶的相互作用.
主要成果:
- 五种化合物表现出显著的ZIKV抑制 (选择性指数>4.6).
- 化合物9b表现出最强烈的活性 (SI = 22.4,EC50 = 25.6 μM).
- 化合物9b,10b,12,17a和19a在盐水测定中显示出低毒性 (MLD 87.2-100.3μg/mL).
- 化合物9b作为ZIKVNS2B-NS3蛋白酶的非竞争性抑制剂,与关键活性部位残留物结合.
- 药模拟确定了额外的潜在蛋白酶抑制剂,其中六个通过模拟证实.
结论:
- 新的pyrazolo[3,4-d]pyridazine-7-one衍生物显示出作为抗ZIKV药物的承诺.
- 化合物9b是进一步开发的有力主要候选物.
- 准ZIKV NS2B-NS3蛋白酶是抗病毒药物发现的可行策略.
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