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BackgroundSigma (σ) receptors are membrane-bound proteins characterised by an unusual promiscuous ability to bind a wide variety of drugs and their high affinity for typical neuroleptic drugs, such as haloperidol, and their potential as alternative targets for antipsychotic agents. Sigma receptors display diverse biological activities and represent potential fruitful targets for therapeutic development in combating many human diseases. Therefore, they present an interesting avenue for further exploration. It was our goal to evaluate the potential of ring opened spipethiane (1) analogues as functional ligands (agonists) for σ receptors by chemical modification.ResultsChemical modification of the core structure of the lead compound, (1), by replacement of the sulphur atom with a carbonyl group, hydroxyl group and 3-bromobenzylamine with the simultaneous presence of 4-fluorobenzoyl replacing the spirofusion afforded novel potent sigma-1 receptor ligands 7a–f, 8a–f and 9d–e. The sigma-1 receptor affinities of 7e, 8a and 8f were slightly lower than that of 1 and their selectivities for this receptor two to threefold greater than that of 1.ConclusionsIt was found that these compounds have higher selectivities for sigma-1 receptors compared to 1. Quantitatitive structure–activity relationship studies revealed that sigma-1 binding is driven by hydrophobic interactions.Graphical abstractIdentified pharmacophore features for sigma binding.Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-016-0200-1) contains supplementary material, which is available to authorized users.

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.

Phytochemical investigation of the crude methanolic extract of the leaves of Tapinanthus pentagonia (Loranthaceae) resulted in the isolation of four known flavonoids namely, quercetin 4’-methylether (1), 4’-methoxy-3’,5,7-trihydroxyflavone (2), quercetin-3-O-rhamnoside (3) and quercetin 3-O-rhamnoside4’- methylether (4). The structures of the isolated compounds were elucidated based on their 1D and 2D-NMR data. This is the first phytochemical study of that plant. The DPPH(2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity, ABTS scavenging activity and ferric reducing antioxidant power (FRAP) were used to assess the antioxidant activities of the crude extract and three of the isolated compounds using catechin, ascorbic acid and gallic acid as standards, respectively. Results of the findings revealed that compound 3 exhibited the highest antioxidant activity in the three tests based on its IC50values followed by compound 4. Its IC50 value was 0.024 mg/ml comparable to that of catechin (0.015 mg/ml) for the radical scavenging activity. In summary, compounds 1, 3 and 4 exhibited good antioxidant properties and reducing power compared to the crude methanolic extract.