抗疟疾化合物的正电荷释放了广谱抗菌活性
Maria Braun-Cornejo1,2,3, Mitchell Platteschorre1, Vincent de Vries1
1Specs Compound Handling, B.V., Bleiswijkseweg 55, Zoetermeer 2712 PB, The Netherlands.
JACS Au
|March 28, 2025
概括
将可电离原子引入抗疟疾化合物,制造出符合 eNTRy 规则的药物. 这些化合物表现出广泛的抗菌活性,对抗阴性细菌和增强的抗疟疾疗效.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 抗菌研究 抗菌研究
背景情况:
- 开发针对格拉姆阴性细菌 (GNB) 的药物是具有挑战性的,因为它们难以穿透细胞外.
- 在eNTRy规则 (电离性,低三维,刚性) 提供结构指导方针,以提高GNB积累.
- 现有的抗疟疾化合物可以修改以向细菌病原体.
研究的目的:
- 为了合成和评估符合 eNTRy规则的化合物,用于广泛的抗微生物活性.
- 调查电离引入对抗菌和抗疟疾疗效的影响.
- 验证eNTRy规则作为开发新型抗菌剂的战略.
主要方法:
- 合成了一种包含氨基和瓜尼丁的pyrazole-amide衍生物库,以符合eNTRy规则.
- 对一组病原体进行了表型查,包括格拉姆阴性细菌,格拉姆阳性细菌,* Mycobacterium tuberculosis* 和 * Plasmodium falciparum*.
- 将符合 eNTRy 规则的化合物的活性与不符合规则的类似物进行比较.
主要成果:
- 符合eNTRy规则的化合物表现出广泛的活性,可以对抗阴性和阳性细菌,M.结核病和P. falciparum.
- 对*P. falciparum*的活性增强到两位数的纳米分子范围.
- 符合标准的化合物显示出测试细菌的显著增长抑制 (微分子范围),而不符合标准的化合物则不活跃.
- 皮拉胺类证明了对eNTRy规则的遵守,支持其实用性.
结论:
- 根据eNTRy规则引入可电离原子是开发广谱抗菌剂的有效策略.
- 这种方法增强了对抗具有挑战性的病原体的活性,例如格拉姆阴性细菌和*M.结核病*.
- 这些发现支持并扩大了eNTRy规则在传染病药物发现中的适用性.
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