Resistances against commonly used antimalarial drugs have resulted in a surge in the number of malaria cases in recent years. This emerging resistance has posed a significant challenge to malaria control programs. Thus, the discovery of new drug candidates with new mechanisms of action is important.

Kishor Mohanan, Renu Tripathi, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, India, and colleagues have identified a new class of 4-aminoquinoline-trifluoromethyltriazoline compounds (general structure pictured) as possible antiplasmodial agents (i.e., compounds that are active against the parasite that causes malaria). A small library of these compounds was prepared via a silver-catalyzed three-component reaction of trifluorodiazoethane with a Schiff base generated in situ from the corresponding quinolinyl amines and aldehydes.

A series of 32 compounds was tested against both chloroquine-sensitive and chloroquine-resistant strains of the malaria parasite. Chloroquine phosphate is used to prevent and treat malaria. Among them, four compounds were found to be potent with IC₅₀ values of 4–20 nM against a chloroquine-sensitive and 120-450 nM against a chloroquine-resistant strain, respectively. One of these candidates was also found to be effective in a mouse model, showing a 99.9 % decrease in parasitic load at day 7 post-infection, along with a 40 % cure rate. Overall, the work indicates that the incorporation of a trifluoromethylated triazoline unit can lead to promising antiplasmodial activity in this compound class.

• Incorporation of Trifluoromethyltriazoline in the Side Chain of 4‐Aminoquinolines: Synthesis and Evaluation as Antiplasmodial Agents,
  Kanchan Yadav, Anamika Sharma, Salique Hassan Shaham, Sanoop P Chandrasekharan, Sandeep Kumar, Anamika Dhami, Hisana Nasreen, Kishor Mohanan, Renu Tripathi,
  ChemMedChem 2023.
  https://doi.org/10.1002/cmdc.202200653