Photopharmacology of Quinoline and Benzimidazole Azobenzene-Based Photoswitchable β‑Hematin Inhibitors.

Recent advances in antimicrobial drug design have incorporated photopharmacology to control drug behavior through light activation, alongside traditional phenotypical strategies including molecular hybridization and metal incorporation. The quinoline and benzimidazole scaffolds are important chemical frameworks identified by the Medicines for Malaria Venture and are known to exert their antiplasmodial activity by inhibiting hemozoin formation, an important target in antimalarial drug design. These scaffolds form part of growing libraries in drug discovery, aimed at developing novel and potent antimalarial agents through structural modifications that improve pharmacological profiles and overcome drug resistance. Consequently, in this study, azobenzene photoswitchable chemical entities have been integrated with quinoline and benzimidazole scaffolds through rational design, aiming to investigate their interactions with hemozoin. The photoswitchable inhibitors showed excellent photo fatigue resistance and thermal relaxation rates exceeding 13 h at 37 °C. In vitro analysis against chloroquine-sensitive NF54 and multidrug-resistant K1 Plasmodium falciparum strains revealed low micromolar activity against the K1 strain. Most notably, this study culminated in two benzimidazole-containing compounds that exhibited differing levels of β-hematin inhibition upon light exposure. Density functional theory calculations and molecular docking studies provided mechanistic insights into how photoisomerization modulates molecular reactivity and hemozoin binding affinity, highlighting the potential of these compounds to be used as light-activated antiplasmodials.