Antifungal Compounds from the Leaves of Rhynchosia minima.

Rhynchosia minima, commonly known as jumby bean, is used as a remedy for respiratory ailments in various parts of the world. It is also used by South African traditional healers to treat heart or chest pain. This study aimed to investigate the bioactive constituents of the leaf extracts of R. minima against selected fungal isolates that have been identified as risk factors in respiratory illness. Rhynchosia minima leaves were extracted sequentially using hexane, dichloromethane, ethyl acetate and methanol in increasing order of polarity. The extracts were subjected to repeated chromatographic techniques, for phytochemical isolation. The extracts and isolated compounds were screened against Candida albicans and Cryptococcus neoformans by determining the minimum concentration that inhibited fungal growth. Six flavonoids, one norisoprenoid and one cyclitol were isolated and characterized by 1D and 2D NMR and HR-ESI-MS. The extracts obtained in the study had moderate to weak antifungal activities, with MICs ranging from 312.5 to 1250.0 µg/mL against both fungi. Four isolated compounds were also screened, with two of them exhibiting activity against C. albicans (MIC=6.25 µg/mL) that was comparable to amphotericin B, the positive control. These two compounds also had better antifungal potential against C. neoformans with an MIC=6.25 µg/mL, compared to the MIC of 12.5 µg/mL of amphotericin B. Seven of the eight isolated compounds were obtained from the extracts of Rhynchosia minima for the first time. Two of the isolated compounds demonstrated activity comparable or superior to amphotericin B activity. The notable potency displayed by these compounds warrants further investigation on their development as antifungal agents.

Secondary metabolites of the leaves of Tricalysia atherura N. Hallé (Rubiaceae) and their potential antiplasmodial activity.

One monoterpene indole alkaloid, atheruramine (1) bearing an ether bridge linking, one hydrobenzoin derivative, tricalydioloside (2) and two ursane-type triterpenes, atherurosides (A and B) (3 and 4) were isolated from the leaves of Tricalysia atherura, together with eight known compounds. The structures of these new compounds were elucidated on the basis of the results of spectroscopic analysis, and the relative configurations of compounds 1-3 were established by NOE difference. Four of the metabolites were screened in vitro against both chloroquine (CQ)-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum; they were found to exhibit moderate activity against chloroquine-resistant (Dd2) (IC50 64.99-92.29 µg/mL). Meanwhile, crude extract possesses high antiplasmodial activity against both 3D7 and Dd2 strains of P. falciparum (IC50 4.39-7.54 µg/mL) and high selectivity indices values (SI > 10) and was found to be safe.

Rational Optimization of Dihydropyrimidinone-Quinoline Hybrids as Plasmodium falciparum Glutathione Reductase Inhibitors.

A series of dihydropyrimidinone-based antimalarial compounds were designed and synthesised based on the previously identified amide-based quinoline hybrids which showed good resistance reversal ability against the resistant strain of Plasmodium falciparum. The aromatic ring on the dihydropyrimidinone of the original hits was exchanged for a methyl group to bring the molecular weights below 500 Da and also determine the effect of the aromatic ring count on the resistance reversal ability of the hybrids. Apart from the previously used amide bond, the hybrid linker was also extended to the triazole linker. Although the triazole linker is synthetically easier to access, the use of an amide linker seems to have an activity advantage. The synthesised compounds in addition to the previously identified hits were subjected to molecular docking particularly targeting the orthosteric site of Plasmodium falciparum glutathione reductase (PfGR) protein. The ligand with the best binding interaction was rationally optimised to increase its suitability as a competitive inhibitor against the cofactor of the PfGR. Two of the optimised ligands showed better binding affinities than the cofactor while one of the two ligands displayed hydrophobically packed correlated hydrogen-bond which is very important in maintaining the ligand stability within the protein. In silico ADME predictions of the synthesised compounds indicate that these compounds possess good pharmacokinetic properties.

In silico design, chemical synthesis and biological screening of novel 4-(1H)-pyridone-based antimalarial agents.

Identifying novel lead compounds in drug discovery has been challenging because of the rapid rise of drug resistance to the existing chemotherapeutics and a lack of understanding of complex metabolic pathways in the parasite. Integrating computational and experimental approaches has shown to be of great worth in identifying and developing novel promising pharmacophore hybrids. In this present research, a series of new 4-(1H)-pyridone-derived antimalarial agents were designed based on recent reports and our preliminary findings through in silico studies. Two of the 4-(1H)-Pyridone derivatives showed potential to bind to the Q0 site of the cytochrome bc1 complex and disrupt the mitochondrial electron transport chain. These compounds, along with previously synthesized compounds, exhibited significant inhibitory activities against the malaria parasite. Presently, seven compounds were successfully synthesized, characterized and these novel compounds have shown promise as antimalarial agents.

Antibacterial and cytotoxic activities of undescribed cassiaric acid and other constituents from Cassia arereh stem barks.

A new lupane-type triterpene, 2α,3ß-dihydroxylupan-29-oic acid (1), and one new ceramide derivative: (2S*,2'R*,3S*,4R*,5R*,7'E,11E,12'E,20E)-N-[2'-hydroxyoctadeca-6,11-dienoyl]-2-aminohexacosa-11,20-diene-1,3,4,5-tetrol (2) were isolated from the ethyl acetate fraction obtained from the methanol extract of the stem barks of Cassia arereh together with seven known compounds. Their structures were characterized using two-dimensional NMR, mass spectrometry, and compared with reported data. To date, this is the first report of the isolation of a multiple double bonds sphingolipid type (2) from this genus. The ethyl acetate extract and selected isolates were examined for antimicrobial and cytotoxic activities in vitro. Betulinaldehyde (5) has shown to be active against all bacterial strains whereas, cassiaric acid (1) and betulinic acid (6) have demonstrated to be moderately active. In addition, cassiaric acid (1) showed the best cytotoxic result against HeLa and MCF-7 cell lines tested with IC50 75.00 µM, while lupeol (3) and betulinic acid (6) displayed weak cytotoxicity at 100.00 µM.

Potential of South African medicinal plants targeting the reduction of Aß42 protein as a treatment of Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Twenty South African medicinal plant species were selected by conducting a literature review based on the relevant information of their reported traditional medicinal uses and scientific reports against Alzheimer's disease, dementia, anxiety, mental illness, depression, acetylcholinesterase inhibition, headache, epilepsy, convulsion, hysteria, and sedative effects. AIM OF STUDY: The goal of this study was to investigate the biological activity of the traditionally used medicinal plant extracts against Alzheimer's disease by in vitro screening of the extracts to determine their potential to decrease levels of Aß42 protein. MATERIAL AND METHODS: Different plant parts (leaves, stem, bark, and stalks) of twenty selected plants were collected from the Manie van der Schijff Botanical Garden, University of Pretoria. Plant parts were dried, ground and then extracted using DCM:MeOH (1:1). We measured the levels of ß-amyloid precursor protein proteolytic products in HeLa cells stably transfected with APP carrying the Swedish mutation using ELISA. RESULTS: Of 33 plant extract 10 (30.3%) were found active based on the potential to significantly reduce the production of Aß42. Amongst them extracts of leaves of Xysmalobium undulatum (Apocynaceae), leaves of Cussonia paniculata (Araliaceae) and leaves of Schotia brachypetala (Fabaceae) potently decreased the production of Aß42 by 77.3 ±â€¯0.5%, 57.5 ±â€¯1.3%, and 44.8 ±â€¯0.1%, respectively. X. undulatum and S. brachypetala enhanced non-amyloidogenic processing of ß-amyloid precursor protein, thereby decreasing Aß42 level. We also showed that C. paniculata induced the decrease of Aß42 level through inhibiting APP processing. In addition, we isolated two cardenolides, compound [A] and [B], from X. undulatum and found that they potently decreased the Aß42 production. CONCLUSION: These data suggest that the extract of X. undulatum, C. paniculata, and S. brachypetala have potential to be developed for Alzheimer's disease treatment. These active extracts and compounds are considered for further studies which examine their efficacy towards the reduction of Aß42 through inhibiting APP process.

Antimalarial pyrido[1,2-a]benzimidazoles.

A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 µM v 0.17 µM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.