Design and synthesis of 7-chloroquinoline-derivative-bearing urea, carbamate, or thiourea moieties and their antimalarial activity against Plasmodium berghei via the inhibition of β-hematin formation

We describe a short synthetic route to a new series of 7-chloroquinoline hybrids derived from albendazole-, thioacetazone-, and primaquine-based drugs. The design strategy incorporated a ureido group as a bioisostere of known inhibitors of β-hematin formation (βHF). Compounds 13 – 34 were characterized by infrared (IR), nuclear magnetic resonance (NMR), and elemental analysis. Preliminary in vitro screening identified compounds 13 , 14 , 16 – 18 , and 27 – 29 as inhibitors of βHF. Among these, compound 16 was the most active, exhibiting 90.68% ± 0.043% inhibition of βHF compared with 92.55% ± 0.019% for chloroquine (CQ). In vivo evaluation in Plasmodium berghei ANKA, a CQ-susceptible murine malaria strain, revealed that compound 16 reduced parasitemia to 1.2% ± 0.12% and extended survival to 27.33 ± 0.15 days. This compares favorably with chloroquine (parasitemia: 0.88% ± 0.09%; survival: 29.6 ± 0.13 days). Furthermore, at a tested concentration of 10 mM, compound 16 showed 17.23 ± 0.13 hemolysis, compared to 29.65 ± 0.10% for CQ, indicating no marked lytic action on erythrocytes. This study evaluated the hepatological consequences of malaria infection in mice infected with P . berghei . Based on its potent in vitro and in vivo activity, favorable hemolytic profile, and hepatoprotective effects, compound 16 emerges as a promising new candidate for antimalarial development.