Antimalarial Quinacrine and Chloroquine Lose Their Activity by Decreasing Cationic Amphiphilic Structure with a Slight Decrease in pH
Antimalarial Quinacrine and Chloroquine Lose Their Activity by Decreasing Cationic Amphiphilic Structure with a Slight Decrease in pH
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DOI：
10.1021/acs.jmedchem.0c02056
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发表时间：
2021-03-27
影响因子：
7.3
通讯作者：
Uesono, Yukifumi
中科院分区：
文献类型：
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作者：
Kitagawa, Tomohisa;Matsumoto, Atsushi;Uesono, Yukifumi
Quinacrine （QC）和chloroquine （CQ）具有抗微生物和抗病毒活性以及抗疟疾活性，尽管其机制尚不清楚。随着阳离子两亲性药物（CAD）结构的ph依赖性增加，QC对酵母的抗菌活性呈指数增长。CAD-QC定位于酵母膜，通过非竞争性抑制葡萄糖摄取诱导葡萄糖饥饿，与抗精神病药氯丙嗪（CPZ）一样。CQ的抗菌活性随着ph依赖性CAD的形成呈指数增长，这表明CAD结构对其药理活性至关重要。当pH值从7.4略微降低时，CAD结构的减少大大降低了它们的效果；即这些药物对恶性疟疾和COVID-19肺炎酸中毒患者无效，导致耐药性。在生理pH值下，没有观察到奎宁、伯氨喹或甲氟喹的CAD结构降低。因此，恢复正常的血液pH值或使用对pH不敏感的喹啉类药物可能对这些感染性酸中毒有效。
Quinacrine (QC) and chloroquine (CQ) have antimicrobial and antiviral activities as well as antimalarial activity, although the mechanisms remain unknown. QC increased the antimicrobial activity against yeast exponentially with a pH-dependent increase in the cationic amphiphilic drug (CAD) structure. CAD-QC localized in the yeast membranes and induced glucose starvation by noncompetitively inhibiting glucose uptake as antipsychotic chlorpromazine (CPZ) did. An exponential increase in antimicrobial activity with pH-dependent CAD formation was also observed for CQ, indicating that the CAD structure is crucial for its pharmacological activity. A decrease in CAD structure with a slight decrease in pH from 7.4 greatly reduced their effects; namely, these drugs would inefficiently act on falciparum malaria and COVID-19 pneumonia patients with acidosis, resulting in resistance. The decrease in CAD structure at physiological pH was not observed for quinine, primaquine, or mefloquine. Therefore, restoring the normal blood pH or using pH-insensitive quinoline drugs might be effective for these infectious diseases with acidosis.