BackgroundEmergence of resistance to artemisinins and some of their combinations in chemotherapy of clinical malaria has intensified the search for novel safe efficacious antimalarial molecules. Fourteen synthetic 1, 4-disubstituted piperidines with simple molecular structures were evaluated in this study.MethodsAntiplasmodial activity were determined against cultured chloroquine-sensitive 3D7 and resistant Dd2 strains of P. falciparum by in vitro parasite growth inhibition. A primary screen was done to identify active compounds by fluorescence microscopy followed by a secondary screen to determine IC50 and IC90 values of active compounds by the parasite lactate dehydrogenase assay. Cytotoxicity of active compounds was assessed using the MTT/formazan assay and selectivity indices (SIs) determined. Optical densities were analysed to obtain experimental results.ResultsThe compounds produced 56 to 93% inhibition of parasite growth at 40 μg/mL. Eight compounds (2 ketone, 5 alcohol and one amine analogues) showed high activity (IC50s between 1 and 5 μg/mL). Nine compounds were highly selective for the parasite (SIs = 15 to 182). Three promising (alcohol) analogues were identified: [1-(4-fluorobenzyl) piperidin-4-yl] [4-fluorophenyl] methanol, (7), [1-(3, 4-dichlorobenzyl) piperidin-4-yl] [4- fluorophenyl] methanol (8) and [1-(4-bromobenzyl) piperidin-4-yl] [4- fluorophenyl] methanol (11) which were more active on the resistant strain (IC50 values between 1.03 to 2.52 μg/mL), than the sensitive strain (IC50 values between 2.51 to 4.43 μg/mL).ConclusionsThe alcohol analogues were the most active and most selective for the parasite with three promising hit molecules identified among them, suggesting the hydroxyl group at C-7’ in these alcohol analogues is contributing greatly to their antiplasmodial activity. Further exploration of the core structure using chemistry approaches and biological screening including in vivo studies in an animal model of malaria may yield important antimalarial leads.

Introduction: Terminalia species have the potential to be exploited in phytomedicine based on their several pharmacological properties including antiplasmodial activity. However, there is need for more data on their antiplasmodial activity and toxicity. This study evaluated the antiplasmodial activities of Terminalia catappa and Terminalia superba found in the coastal area of Cameroon on resistant strains of Plasmodium falciparum not previously tested, and their toxicity. Methods: Three leaf extracts of each plant prepared separately using three organic solvents were screened in vitro on 3 strains of P. falciparum: chloroquine-sensitive 3D7, chloroquine-resistant Dd2 and multi-drug resistant W2mef using the parasite growth inhibition assay. Antiplasmodial activity was assessed using fluorescence microscopy and the parasite lactate dehydrogenase assay. Cytotoxicity of active extracts was assessed on LLC-MK2 monkey kidney epithelial cells and acute toxicity including effect on some liver enzymes in BALB/c mice. Results: The methanol extracts of both plants showed the highest antiplasmodial activity (IC50 between 5.03-9.76 μg/mL) on the three parasite strains. The methanol extracts showed high selectivity for parasites with selectivity index values ranging from 40 to 80 indicating very low risk of toxicity. There was no mortality or adverse effect and no significant effect on the liver enzymes, alanine aminotransferase (P = 0.506) and aspartate aminotransferase (P = 0.243). Conclusion: The antiplasmodial activity, high selectivity and no adverse effects for T. catappa and T. superba demonstrate the potential for use of these plants in traditional treatment of malaria, further development into a phytomedicine against malaria and as source of new antimalarial lead.