Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Med Chem. 2021 Apr 8;64(7):3885-3896. doi: 10.1021/acs.jmedchem.0c02056. Epub 2021 Mar 27.
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.
盐酸奎宁（QC）和氯喹（CQ）具有抗菌、抗病毒和抗疟作用，但其作用机制尚不清楚。QC 可使阳离子两亲性药物（CAD）结构随 pH 值的增加呈指数增加，从而使抗真菌药物的抗菌活性呈指数增加。CAD-QC 定位于酵母细胞膜上，并通过非竞争性抑制葡萄糖摄取（如抗精神病药氯丙嗪（CPZ））来诱导葡萄糖饥饿。CQ 也表现出与 pH 依赖性 CAD 形成呈指数增加的抗菌活性，表明 CAD 结构对其药理活性至关重要。从 7.4 略微降低 pH 值会导致 CAD 结构减少，从而大大降低其效果；也就是说，这些药物在酸中毒的恶性疟原虫疟疾和 COVID-19 肺炎患者中作用效率低下，导致耐药性。在生理 pH 值下，不会观察到奎宁、伯氨喹或甲氟喹的 CAD 结构减少。因此，恢复正常的血液 pH 值或使用 pH 不敏感的喹啉类药物可能对这些酸中毒相关的传染病有效。
