Quinoline as Lead Structures for the Development of Leishmanicidal Agents

Angel Romero^1*Gustavo Benaim^2,3

• ¹Universidad de la República, Montevideo, Uruguay
• ²Fundacion Instituto de Estudios Avanzados IDEA, Caracas, Venezuela
• ³Universidad Central de Venezuela Instituto de Biologia Experimental, Caracas, Venezuela

aniline moiety at the 4-position showed to be more favoured than amine-alkyl chain. In general, some 4-aminoquinolines were characterized by promoting a depolarization of parasite mitochondrial potential inducing apoptosis and morphologic changes in the parasite. Production of nitric oxide and increase of proinflammatory cytokines in the infected macrophage models suggest an immunostimulant response of the 4-aminoquinoline compounds against intracellular amastigotes. Promising candidates 1-6 for preclinical studies are shown in Figure 1. Regarding the role of 2-, 3-, 6-and 8-substitution into quinolines (Garcia and Elso, 2025), it should be noted that the inclusion of lipophilic chains like alkenyl or aryl at the 2-, 3-and 6-position favoured significantly the activity and selectivity (7, Figure 1), whereas the incorporation of O-or N-substituent is more preferred for the 8-position. N-substitution at the 2 and 3-position generated compounds having a discrete leishmanicidal response. From the metallic complexes quinoline-based (Del Carpio et al. 2025), there three type of recognized metallic complexes; i) coordination complexes of Sb(V), Ga(III) or V(IV/V) using 8-quinolinols as ligand; ii) chloroquine or primaquine analogues bearing ferrocenyl moiety at the 4-dialkyldiamine chain and; iii) quinolines bearing a metal-NHC moiety. Among them, a water-soluble, selective and potent compound either against in vitro or in vivo models of LV was identified from the group of quinolines bearing ferrocenyl moiety (8, Figure 1). Chloroquine and primaquine nucleus were convenient to generate active and selective quinoline-ferrocenyl leishmanicidal compounds. Quinoline-ferrocenyl compounds promoted oxidative stress, morphological changes and early apoptosis in the parasite and immunostimulation in the infected model. Meanwhile complexes Sb/Ga/V showed a discrete selectivity index (S.I) lower than 15, whereas the quinolines NHC-based were highly toxic and lowly selectivity (S.I. ˂5). Concerning the natural products (Yaluff et al. 2025), there are a few examples in the literature about the leishmanicidal responsed of natural quinolines. Most of the examples are focused on 2-alkylquinolines, being the inclusion either of alkyl chain or of aryl chain key to generate active and potent leishmanicidal agents, which support even more the tendency found in synthetic 2-substituted quinolines (Garcia and Elso, 2025). Regarding the antimalarial quinolines (Avanzo et al., 2025), most of the studied are focused on chloroquine and sitamaquine, showing excellent clinical results. Others such as primaquine and amodiaquine have shown a great potential for further preclinical studies, whereas ferroquine showed to be the least prominent antimalarial. The use of a delivery drug system (DDS) to encapsulate and improve the efficacy of leishmanicidal quinolines was discussed (Romero et al. 2025). The particle size, type of DDS, nature of the polymeric matrix plays an important role in the design of micro/nanoformulation. The encapsulation of quinolines is concentrated on polymeric NPs and liposomes. Most of the studied cases were applied against VL models. NPs based on PLGA and liposomes emerge as the most convenient DDS to give good pharmacokinetic/therapeutic profiles. Figure 1. Promising quinoline candidate for preclinical studies. The role of the lipophilicity and acidity, that must be pivotal in the design of leishmanicidal agents in order to seek the drug accumulation into phagolysosome, was analysed in the topic, finding Log P~4-6 and pKa2 ~8-9 as optimal parameters for generating highly active and selective quinolines (Romero, 2025b). Finally, a full recompilation of synthetic strategies and their reactions to access to the highly versatile 4-quinoline was discussed (Delgado et al. 2025). The reactions are based on: (i) nucleophilic aromatic substitution via conventional heating, microwave, and ultrasound; (ii) one-pot metal-free or metal-catalyzed inter-and intramolecular cyclization/annulation; (iii) miscellaneous reactions including dehydrogenative amination of dihydroquinolin-4(1H)one, amination via Hartwig-Buchwald cross coupling and rearrangement reactions. In summary, the review/minireviews/opinion articles presented in this Research Topic collectively highlight the potential of the quinoline as scaffold for the design of potent and selective leishmanicidal agents. Structure-activity, role of the quinoline-substitution, mechanism aspects, immune issues, synthetic aspect, role of the nanotechnology and physicochemical aspects (lipophilicity and acidity) contributed significantly to show the broad window of the quinoline as a privileged scaffold. Then, the insights provided in this Research Topic represents an invaluable resource for researchers and clinicians working toward the development of more effective leishmanicidal agents, in particular, based on quinolines.