A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 μM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 μM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 μM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

Biotechnology Unit Faculty of Pharmacy Central University of Venezuela Los Chaguaramos 1041 A Caracas 1040 Venezuela

Escuela de Medicina Universidad Espíritu Santo Samborondón Guayas Guayaquil 092301 Ecuador

Facultad de Ciencias de la Salud y Desarrollo Humano Univesidad Ecotec Km 13 5 Samborondón Guayas Guayaquil 092302 Ecuador

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Hněvotínská 1333 5 779 00 Olomouc Czech Republic

Instituto de Biología Experimental Facultad de Ciencias Central University of Venezuela Caracas 1040 Venezuela

Organic Synthesis Laboratory Faculty of Pharmacy Central University of Venezuela Los Chaguaramos 1041 A Caracas 1040 Venezuela

Unidad de Bioquímica de Parásitos y Señalización Celular Instituto de Estudios Avanzados Caracas 1080 Venezuela

Unidad de Bioquímica Facultad de Farmacia Central University of Venezuela Los Chaguaramos 1041 A Caracas 1040 Venezuela

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