Abstract
Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.
Highlights
Malaysia has made significant progress in the control of malaria
The combination of both 4-aminoquinoline and pyrano[2,3c]pyrazole has increased the potency of 4b against the K1 and 3D7 strains. We suggest that both quinolines and pyrazole pharmacophores are responsible for the antimalarial effects shown by 4b
Because P. falciparum highly depends on glycolysis for energy production, we hypothesize that hybrid molecules 4a–e exerted the antimalarial effects by inhibiting the activity of Plasmodium falciparum lactate dehydrogenase (PfLDH)
Summary
Malaysia has made significant progress in the control of malaria. the fatality rate fluctuated throughout the period 2001–2012. Joubert et al [7] showed that drug-likeliness characteristics in artemisinin-acridine hybrids have extremely low solubility and absorption levels under physiological conditions and undefined blood-brain barrier penetration levels They later proposed that blocking polar primary/secondary amine groups in the intermediates reduces hydrogen bond formation. Isatin derivatives were functionalized with the thiosemicarbazone moiety that could inhibit P. falciparum-derived cysteine proteases [13] These proteins are essential for the degradation of hemoglobin during erythrocytic parasite development. The 4-amino groups will be linked with the ethyl chain (two carbon atoms) that may increase activity against chloroquine-resistant strains. Hybrids with a linker chain whereas the isatin group inhibits P. falciparum cysteine proteases. Most of and the published studies on the design and synthesis of antimalarial hybrids and pyrimidine isatin derivatives, were introduced to help with the drug resistance.
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