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

Background/Objectives: Malaria remains the most critical parasitic disease globally, responsible for over 600.000 deaths annually. In sub-Saharan Africa, co-infections of Plasmodium falciparum with other pathogens, particularly Staphylococcus aureus, are common in children with severe malaria. Therefore, the design of new compounds targeting both pathogens appears to be an urgent priority. Methods: 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. Results: Compounds 4b and 5b emerged the most potent candidates of the series, showing a sub-micromolar inhibitory activity on P. falciparum, and a promising micromolar potency on S. aureus 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. Conclusions: 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.