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Background: A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). Methods: Natural products with in vitro antiplasmodial activities (NAA) were compiled from various sources. These natural products were sub-divided into four groups based on inhibitory concentration (IC50). Key molecular descriptors and physicochemical properties were computed for these compounds and analysis of variance used to assess statistical significance amongst the sets of compounds. Molecular similarity analysis, estimation of drug-likeness, in silico pharmacokinetic profiling, and exploration of structure--activity landscape were also carried out on these sets of compounds. Results: A total of 1040 natural products were selected and a total of 13 molecular descriptors were analysed. Significant differences were observed among the sub-groups of NAA and CRAD for at least 11 of the molecular descriptors, including number of hydrogen bond donors and acceptors, molecular weight, polar and hydrophobic surface areas, chiral centres, oxygen and nitrogen atoms, and shape index. The remaining molecular descriptors, including clogP, number of rotatable bonds and number of aromatic rings, did not show any significant difference when comparing the two compound sets. Molecular similarity and chemical space analysis identified natural products that were structurally diverse from CRAD. Prediction of the pharmacokinetic properties and drug-likeness of these natural products identified over 50 % with desirable drug-like properties. Nearly 70 % of all natural products were identified as potentially promiscuous compounds. Structure--activity landscape analysis highlighted compound pairs that form 'activity cliffs'. In all, prioritization strategies for the NAA were proposed. Conclusions: Chemo-informatic profiling of NAA and CRAD have produced a wealth of information that may guide decisions and facilitate anti-malarial drug development from natural products. Articulation of the information provided within an interactive data-mining environment led to a prioritized list of NAA. [ABSTRACT FROM AUTHOR]

Background: Access to useful plants is a growing problem in Africa, increased by the loss of natural vegetation and the erosion of traditional knowledge. Ethnobotany contributes to promote these indigenous knowledge. Despite the large diversity of ethnic groups in Côte d'Ivoire, few ethnomedicine researches have targeted these groups. Among the great Akan group, the Ehotile people are one of the smallest and oldest ethnic group around the Aby Lagoon. The goal of this study was to analyze the level of knowledge and use of medicinal plants by the Ehotile people, and moreover, contribute to build a database about useful plants of first Ivorian people. Methods: Two sets of surveys were conducted in four Ehotile villages: a house-to-house freelist interview and an individual walk-in-the woods interview with some key informants identified by the community. Frequency of citation, Smith's index, Use value and Informant Consensus Factor were used to estimate the local knowledge of medicinal plants. Results: Medicinal plants are widely used by Ehotile people. Some were used in addition to modern prescriptions while for some disorders commonly called "African diseases" only plants are used. 123 species employed in the treatment of 57 diseases were listed. Specifically, the most common indications included malaria, sexual asthenia, troubles linked to pregnancy, dysmenorrhoea and haemorrhoids. Analysis of freelists suggested that Ehotile people has a good knowledge of medicinal plants and the most salient included Harungana madagascariensis, Alstonia boonei, Ocimum gratissimum and Xylopia acutiflora. Regarding the consensus among key informants, ICF values were low (<0.5), however category of infectious and parasitic diseases obtained the best agreement (ICF = 0.42). Following the local experts, 4 types of plants availability were distinguished: Abundant plants easy to collect, abundant plants difficult to harvest, scarce plants and endangered plants. Conclusions: Despite the virtual disappearance of natural formations in Ehotile land, medicinal plants are important in the Ehotile health system. Medicinal plants are known and used alone or in addition to medical prescriptions to treat several ailments. However, some of them are becoming rare, and it is feared that this scarcity will result in the inevitable loss of associated knowledge and practices. [ABSTRACT FROM AUTHOR]

In previous studies, the polycyclic cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane (NGP1-01) and a number of its derivatives showed positive effects in neuroprotection studies with MPTP, in vivo. In view of these findings, we examined these compounds for their effects on [3H]dopamine ([3H]DA) release and uptake inhibition in murine striatal synaptosomes, as well as for inhibition of baboon liver monoamine oxidase (MAO) B. In order to assess specificity, initial experiments focused on compounds that blocked dopamine uptake without causing appreciable release (<40% at 100 μM) of the transmitter. NGP1-01 blocked the uptake of [3H]DA with an IC50 of 57 μM, while another compound, 8-phenylethyl-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane, blocked uptake at an IC50 value of 23 μM. These values were comparable to that of another polycyclic cage amine, amantadine (IC50; 82 μ), that is used in parkinsonian therapy. Structure–activity relationships of this series of compounds support the importance of geometric and steric, rather than electronic effects, in determining biological activity. MAO-B inhibition for this group was weak, with less than 50% inhibition at 300 μM for any of the compounds in the series. The present study suggests that blockage of the dopamine transporter may underlie, at least in part, their neuroprotective effects against MPTP-induced parkinsonism. These compounds may be considered as potential lead compounds for Parkinson''s Disease therapy. [Copyright &y& Elsevier]

Abstract: Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure–activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ 1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q 2) regression value of 0.6, and a non-cross validated r 2 of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r 2 >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ 1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [3H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50 =1.78μM) and its phenethyl derivative (IC50 =1.54μM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ 1) receptor. [Copyright &y& Elsevier]

Abstract: Monoamine oxidase B (MAO-B) and nitric oxide synthase (NOS) have both been implicated in the pathology of neurodegenerative diseases. In an attempt to design dual-target-directed drugs that inhibit both these enzymes, a series of pteridine-2,4-dione analogues were synthesised. The compounds were found to be relatively weak NOS inhibitors but showed promising MAO-B activity with 6-amino-5-[(E)-3-(3-chloro-phenyl)-prop-2-en-(E)-ylideneamino]-1,3-dimethyl-1H-pyrimidine-2,4-dione and 6-[(E)-2-(3-chloro-phenyl)-vinyl]-1,3-dimethyl-1H-pteridine-2,4-dione inhibiting MAO-B with IC50 values of 0.602 and 0.314μM, respectively. The pteridine-2,4-dione analogues thus show promise as scaffolds for the development of potent reversible MAO-B inhibitors and as observed in earlier studies, the most potent inhibitors were obtained with 3-chlorostyryl substitution. [Copyright &y& Elsevier]

The control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarials such as chloroquine (CQ). Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (>50%) and act as a chemosensitizer. Based on this finding we set out to synthesize a small series of novel agents comprising of a PCU moiety as the reversal agent conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as reversed CQ agents. PCU-AM derivatives 1 – 3 showed anti-plasmodial IC 50 values in the ranges of 3.74–17.6 nM and 27.6–253.5 nM against CQ-sensitive (D10) and CQ-resistant strains (Dd2) of Plasmodium falciparum , respectively. Compound 1 presented with the best antiplasmodial activity at low nM concentrations against both strains and was found to be 5 fold more active against the resistant strain than CQ. Compound 1 can be considered as a lead compound to develop reversed CQ agents with improved pharmacodynamic and pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Abstract: Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines. Acute imipramine (IMI, 15mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity). Only IMI, MB (15, 30, 60mg/kg) and MG (7.5, 25, 40mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15mg/kg) increased noradrenergic behaviour in the FST, while MB (15mg/kg) and MG (15mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels. MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal. [ABSTRACT FROM AUTHOR]