Antimalarial drugs lose their activity with a slight drop in pH

Antimalarial drugs have antimicrobial, antiviral, antimalarial and immunosuppressive activities, although the mechanisms remain unknown. Quinacrine (QC) increases the antimicrobial activity against yeast exponentially with a pH-dependent increase in the cationic amphiphilic drug (CAD) structure. CAD-QC localizes in membranes and induces glucose starvation by noncompetitively inhibiting glucose uptake. A logarithmic increase in antimicrobial activity with pH-dependent CAD formation was also observed for chloroquine, 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. Recovering normal blood pH or using pH-insensitive quinoline drugs might be effective.