1,2,3-Triazole derivatives: synthesis, docking, cytotoxicity analysis and in vivo antimalarial activity.

Malaria remains one of the most important parasitic diseases in the world. The multidrug-resistant Plasmodium strains make the treatment currently available for malaria less effective. Therefore, the development of new drugs is necessary to overcome therapy resistance. Triazole derivatives exhibit several biological activities and provide a moiety that is promising from the biological perspective. Due to the structural similarity to NADH, it is believed that triazoles can bind to the active site of the Plasmodium lactate dehydrogenase (pLDH) enzyme. The present work evaluates the antimalarial activity of 1,2,3-triazole derivatives by in silico, in vitro, and in vivo studies. Preliminary in silico ADMET studies of the compounds demonstrated good pharmacokinetic properties. In silico docking analysis against LDH of Plasmodium berghei (PbLDH) showed that all compounds presented interactions with the catalytic residue in the active site and affinity similar to that presented by chloroquine; the most common antimalarial drug. Cytotoxicity and hemolysis by these derivatives were evaluated in vitro. The compounds 1, 2, 5, 8, and 9 proved to be non-cytotoxic in the performed tests. In vivo antimalarial activity was evaluated using mice infected with Plasmodium berghei NK65. The five compounds tested exhibited antimalarial activity until nine days post-infection. The compound 5 showed promising activities, with about 70% parasitemia suppression. Considering the in vitro and in vivo studies, we believe the compound 5 to be the most promising molecule for further studies in antimalarial chemotherapy.

In vitro and in vivo antiplasmodial activity of novel quinoline derivative compounds by molecular hybridization.

Chloroquine (CQ) has been the main treatment for malaria in regions where there are no resistant strains. Molecular hybridization techniques have been used as a tool in the search for new drugs and was implemented in the present study in an attempt to produce compound candidates to treat malarial infections by CQ-resistant strains. Two groups of molecules were produced from the 4-aminoquinoline ring in conjugation to hydrazones (HQ) and imines (IQ). Physicochemical and pharmacokinetic properties were found to be favorable when analyzed in silico and cytotoxicity and antiplasmodial activity were assayed in vitro and in vivo showing low cytotoxicity and selectiveness to the parasites. Candidates IQ5 and IQ6 showed important values of parasite growth inhibition in vivo on the 5th day after infection (IQ5 15 mg/kg = 72.64% and IQ6 15 mg/kg = 71.15% and 25 mg/kg = 93.7%). IQ6 also showed interaction with ferriprotoporphyrin IX similarly to CQ. The process of applying condensation reactions to yield imines is promising and capable of producing molecules with antiplasmodial activity.

Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to­lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 µM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.