Abstract
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.
Highlights
Emergence of resistance to artemisinins and some of their combinations in chemotherapy of clinical malaria has intensified the search for novel safe efficacious antimalarial molecules
Compounds that displayed greater than 50% inhibition of P. falciparum growth in the primary screen progressed to the secondary assay
The following criteria were adopted for antiplasmodial activity: active, IC50 < 5 μg/mL; moderately active: 5 μg/mL ≤ IC50 ≤ 10 μg/mL; weakly active: IC50 ≥ 10 μg/mL
Summary
Emergence of resistance to artemisinins and some of their combinations in chemotherapy of clinical malaria has intensified the search for novel safe efficacious antimalarial molecules. There is increasing resistance to the other drug classes cited above while delayed parasite clearance to the artemisinins has been detected in five countries of the Greater Mekong, in Southeast Asia along with multi-drug resistance in P. falciparum. In this area delayed parasite clearance has been reported for ACTs where there is resistance to the partner drug and it is thought that artemisinin could facilitate selection for resistance to the partner drug [2, 3]. Whole cell screens are done on blood, liver and transmission stages of the parasite [4]
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