Harnessing the Quinoline Scaffold toward Discovery and Development of Antimalarials

Abstract The quinoline scaffold, a well-established privileged structure, continues to play a central role in antimalarial drug discovery. This perspective presents a comprehensive summary and discussion of the antimalarial targets of quinoline derivatives, including heme detoxification, PfCDPK1, PfChoK, PfPI4K, PfPK6, proteases, PfLDH, PfHSP, PfCRT, PfeEF2, PfPFT, and the cytochrome bc1 complex. Particular emphasis is placed on promising analogs with dual-stage or multistage activity, potent efficacy against drug-resistant Plasmodium falciparum strains, and favorable physicochemical and pharmacokinetic profiles, together with robust in vivo performance. Emerging safety considerations, such as cardiotoxicity (hERG inhibition), hepatotoxicity, and metabolite formation, are also highlighted. In addition, key challenges and future directions are discussed, including exploration of new biological targets and the application of modern discovery strategies such as molecular hybridization, drug repurposing, prodrug design, and ionic liquids. Overall, this perspective aims to provide insights that support the continued development of affordable, safe, and effective quinoline-based antimalarial therapeutics.