Novel saturated 1,2,4-trioxanes and their antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in Swiss mice model via oral route.

Novel saturated 6-(4'-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1-3)-12d(1-3) and 13a(1-3)-13d(1-3) have been designed and synthesized, in one single step from diimide reduction of 11a(1-3)-11d(1-3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1, provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, ß-arteether provides only 20 % protection at 24 mg/kg × 4 days.

The effect of malaria-induced alteration of metabolism on piperaquine disposition in Plasmodium yoelii infected mice and predicted in malaria patients.

OBJECTIVES: Malaria-induced alteration of physiological parameters and pharmacokinetic properties of antimalarial drugs may be clinically relevant. Whether and how malaria alters the disposition of piperaquine (PQ) was investigated in this study. METHODS: The effect of malaria on drug metabolism-related enzymes and PQ pharmacokinetic profiles was studied in Plasmodium yoelii-infected mice in vitro/in vivo. Whether the malaria effect was clinically relevant for PQ was evaluated using a validated physiologically-based pharmacokinetic model with malaria-specific scalars obtained in mice. RESULTS: The infection led to a higher blood-to-plasma partitioning (Rbp) for PQ, which was concentration-dependent and correlated to parasitemia. No significant change in plasma protein binding was found for PQ. Drug metabolism-related genes (CYPs/UDP-glucuronosyltransferase/nuclear receptor, except for CYP2a5) were downregulated in infected mice, especially at the acute phase. The plasma oral clearances (CL/F) of three probe substrates for CYP enzymes were significantly decreased (by ≥35.9%) in mice even with moderate infection. The validated physiologically-based pharmacokinetic model indicated that the hepatic clearance (CLH) of PQ was the determinant of its simulated CL/F, which was predicted to slightly decrease (by ≤23.6%) in severely infected mice but not in malaria patients. The result fitted well with the plasma pharmacokinetics of PQ in infected mice and literature data on malaria patients. The blood clearance of PQ was much lower than its plasma clearance due to its high Rbp. CONCLUSIONS: The malaria-induced alteration of drug metabolism was substrate-dependent, and its impact on the disposition of PQ and maybe other long-acting aminoquinoline antimalarials was not expected to be clinically relevant.

Evaluation of genotoxic damage, production reactive oxygen and nitrogen species in Plasmodium yoelii yoelii exposed to sodium metavanadate.

Malaria represents the greatest global health burden among all parasitic diseases, with drug resistance representing the primary obstacle to control efforts. Sodium metavanadate (NaVO3) exhibits antimalarial activity against the Plasmodium yoelii yoelii (Pyy), yet its precise antimalarial mechanism remains elusive. This study aimed to assess the antimalarial potential of NaVO3, evaluate its genotoxicity, and determine the production of reactive oxygen and nitrogen species (ROS/RNS) in Pyy. CD-1 mice were infected and divided into two groups: one treated orally with NaVO3 (10 mg/kg/day for 4 days) and the other untreated. A 50% decrease in parasitemia was observed in treated mice. All experimental days demonstrated DNA damage in exposed parasites, along with an increase in ROS and RNS on the fifth day, suggesting a possible parasitostatic effect. The results indicate that DNA is a target of NaVO3, but further studies are necessary to fully elucidate the mechanisms underlying its antimalarial activity.

Evaluation of the antiplasmodial efficacy of synthetic 2,5-diphenyloxazole analogs of compounds naturally derived from Oxytropis lanata.

The persistent prevalence and dissemination of drug-resistant malaria parasites continue to challenge the progress of malaria eradication efforts. As a result, there is an urgent need to search for and develop innovative therapies. In this study, we screened synthetic 2,5-diphenyloxazole analogs from Oxytropis lanata. Among 48 compounds, 14 potently inhibited the proliferation of P. falciparum strains 3D7 (chloroquine-sensitive) and K1 (multidrug-resistant) in vitro, exhibited IC50 values from 3.38 to 12.65 µM and 1.27-6.19 µM, respectively, and were toxic to human foreskin fibroblasts at 39.53-336.35 µM. Notably, Compounds 31 (2-(2',3'-dimethoxyphenyl)-5-(2″-hydroxyphenyl)oxazole) and 32 (2-(2',3'-dimethoxyphenyl)-5-(2″-benzyloxyphenyl)oxazole) exhibited the highest selectivity indices (SIs) against both P. falciparum strains (3D7/K1), with values > 40.20/>126.58 and > 41.27/> 59.06, respectively. In the IC50 speed and stage-specific assays, Compounds 31 and 32 showed slow action, along with distinct effects on the ring and trophozoite stages. Microscopy observations further revealed that both compounds impact the development and delay the progression of the trophozoite and schizont stages in P. falciparum 3D7, especially at concentrations 100 times their IC50 values. In a 72-h in vitro exposure experiment at their respective IC80 in P. falciparum 3D7, significant alterations in parasitemia levels were observed compared to the untreated group. In Compound 31-treated cultures, parasites shrank and were unable to reinvade red blood cells (RBCs) during an extended 144-h incubation period, even after compound removal from the culture. In vivo assessments were conducted on P. yoelii 17XNL-infected mice treated with Compounds 31 and 32 at 20 mg/kg administered once daily for ten days. The treated groups showed statistically significant lower peaks of parasitemia (Compound 31-treated: trial 1 12.7%, trial 2 15.8%; Compound 32-treated: trial 1 12.7%, trial 2 14.0%) compared to the untreated group (trial 1 21.7%, trial 2 28.3%). These results emphasize the potential of further developing 2,5-diphenyloxazoles as promising antimalarial agents.