Antimalarial Pyrido[1,2- a]benzimidazole Derivatives with Mannich Base Side Chains: Synthesis, Pharmacological Evaluation, and Reactive Metabolite Trapping Studies.

A novel series of pyrido[1,2- a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum ( P. falciparum) strains. Rapid metabolism was observed for all the analogues with <40% of parent compound remaining after 30 min of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-aminophenol moiety, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodium activity, which was significantly lowered.

Antischistosomal Activity of Pyrido[1,2-a]benzimidazole Derivatives and Correlation with Inhibition of ß-Hematin Formation.

The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit ß-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 µM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between ß-hematin inhibitory and antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most active compound in vivo showed 58.7 and 61.3% total and female worm burden reduction, respectively. Pharmacokinetic analysis suggested solubility-limited absorption and high hepatic clearance as possible contributors to the modest efficacy despite good in vitro activity. The PBIs evaluated in this report thus merit further optimization to improve their efficacy and to elucidate their possible mode of action.

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model.

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Cyclopalladated organosilane-tethered thiosemicarbazones: novel strategies for improving antiplasmodial activity.

Two series of ferrocenyl- and aryl-derived cyclopalladated organosilane thiosemicarbazone complexes were synthesised via C-H bond activation. Selected compounds were evaluated for in vitro antiplasmodial activity against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the human malaria parasite Plasmodium falciparum. Cyclopalladation of the thiosemicarbazones resulted in antiplasmodial activities in the low micromolar range.