Antimalarial Quinacrine and Chloroquine Lose Their Activity by Decreasing Cationic Amphiphilic Structure with a Slight Decrease in pH

Abstract

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 pHdependent 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.

Defending Antiviral Cationic Amphiphilic Drugs That May Cause Drug-Induced Phospholipidosis

“…The alkalinization of acidic components, like the lysosome, in such host cells has previously been proposed as a strategy to decrease SARS-CoV-2 viral infection . Kitagawa et al also discussed the importance of pH on the antimalarial CAD structure which may also impact their antiviral activity . These observations clearly suggest that not all CADs are created equal, and their biological activity may be influenced by other factors.…”

Escaping from the Cutoff Paradox by Accumulating Long-Chain Alcohols in the Cell Membrane

“…CAD-QC and CPZ localize to the yeast cell membrane at neutral pH and inhibit the hexose transporter (Hxt) function noncompetitively, indicating that they interact with the sites other than the hexose recognition site on the membrane. Therefore, these amphiphilic drugs would penetrate nonspecifically into the membrane lipids along the amphiphilic orientation and affect various membrane targets including Hxt with the concentration, by interacting indirectly with them at the lateral side, thereby supporting the lipid theory …”

“…In budding yeast, the amphiphilic compounds, such as the alcohols (C 1 –C 3 ), local anesthetics, antipsychotic phenothiazines, and antimalarial quinoline drugs, induce the glucose starvation reactions such as the inhibition of translation initiation and depolarization of actin cytoskeleton at low concentrations but destroy the cell membrane at high concentrations. ,, As judged by the dose–response curve for actin depolarization, the potencies of these drugs obey the MO correlation, similarly to MICs and LD 50 ’s of alcohols (Figure B). The structures of these electrolytes change between the diprotonated hydrophilic (HP), monoprotonated cationic amphiphilic drug (CAD), and unprotonated lipophilic (LP) forms with pH, except for nonelectrolyte alcohols.…”

“…It is hard to compare the membrane concentrations of alcohols for MIC and LD 50 in yeast because of the different experimental conditions (Table ). In contrast, it is possible to compare the estimated membrane concentrations exerting different effects of the membrane-localized CAD-QC (11.8%) formed at pH 7.5 (logD: 0.99) . These effective doses ( C w ) were evaluated by dose–response curves in the same experimental condition (2.5 × 10 6 cells, 30 min), such as the half inhibitory concentration for actin polarization (IC 50 : 1 mM), the half lethal dose in cells (LD 50 : 2.7–3.7 mM), and the dose initiating cell lysis (21 mM) .…”

“…In contrast, it is possible to compare the estimated membrane concentrations exerting different effects of the membrane-localized CAD-QC (11.8%) formed at pH 7.5 (logD: 0.99) . These effective doses ( C w ) were evaluated by dose–response curves in the same experimental condition (2.5 × 10 6 cells, 30 min), such as the half inhibitory concentration for actin polarization (IC 50 : 1 mM), the half lethal dose in cells (LD 50 : 2.7–3.7 mM), and the dose initiating cell lysis (21 mM) . Thus, these C m values are approximated to 10, 26–36, and 206 mM, respectively, as the product of distribution coefficient ( D : 9.8) and the C w values.…”