STOP Strategy to Inhibit P. falciparum and S. aureus Growth: Molecular Mechanism Studies on Purposely Designed Hybrids

<b>Background/Objectives</b>: Malaria remains the most critical parasitic disease globally, responsible for over 600.000 deaths annually. In sub-Saharan Africa, co-infections of <i>Plasmodium falciparum</i> with other pathogens, particularly <i>Staphylococcus aureus</i>, are common in children with severe malaria. Therefore, the design of new compounds targeting both pathogens appears to be an urgent priority. <b>Methods</b>: A small series of hybrid compounds was designed and synthesized by linking the pharmacophore of the antimalarial drug chloroquine with the phenothiazine core. These compounds were tested in vitro against a panel of microbial strains and further analyzed through in silico simulations to predict their physical-chemical properties. <b>Results</b>: Compounds <b>4b</b> and <b>5b</b> emerged the most potent candidates of the series, showing a sub-micromolar inhibitory activity on <i>P. falciparum</i>, and a promising micromolar potency on <i>S. aureus</i> alongside with a low toxicity on mammalian cells. Molecular docking followed by molecular dynamics (MD) simulations identified the respiratory membrane NDH-2 enzyme as common target in both pathogens. <b>Conclusions</b>: Both experimental and computational findings provide compelling evidence for the use of the designed compounds in a STOP strategy, i.e., Same-Target-Other-Pathogen, to treat malaria and bacterial infections concurrently.