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C18H15BrO4, monoclinic, P21/c (no. 14), a = 14.616(2) Å, b = 14.657(2) Å, c = 7.3864(12) Å, β = 103.627(7)°, V = 1537.8(4) Å3, Z = 4, Rgt(F) = 0.0315, wRref(F2) = 0.0935, T = 100 K.

C24H18O8, monoclinic, P21 (no. 4), a = 7.9654(3) Å, b = 23.6910(8) Å, c = 21.2314(8) Å, β = 96.777(2)°, V = 3978.6(3) Å3, Z = 8, Rgt(F) = 0.0499, wRref(F2) = 0.1320, T = 200 K.

Abstract Background Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. Methods Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase (pLDH) assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications in vitro using the pLDH assay. The effects of the pure compound on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls), followed by oligonucleotide microarray- and data analysis. Results The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 1.865 μM against a chloroquine-sensitive strain (D10) of P. falciparum. Synthetic analogues of the compound confirmed an absolute requirement that the α-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action. Microarray data analysis identified 572 unique genes that were differentially expressed as a result of the treatment and gene ontology analysis identified various biological processes and molecular functions that were significantly affected. Comparison of the dehydrobrachylaenolide treatment transcriptional dataset with a published artesunate (also a sesquiterpene lactone) dataset revealed little overlap. These results strengthen the notion that the isolated compound and the artemisinins have differentiated modes of action. Conclusions The novel mode of action of dehydrobrachylaenolide, detected during these studies, will play an ongoing role in advancing anti-plasmodial drug discovery efforts.

C18H15BrO4, monoclinic, P21/c (no. 14), a = 14.616(2) Å, b = 14.657(2) Å, c = 7.3864(12) Å, β = 103.627(7)°, V = 1537.8(4) Å3, Z = 4, Rgt(F) = 0.0315, wRref(F2) = 0.0935, T = 100 K. [ABSTRACT FROM AUTHOR]

Previous results indicated that the methanol extract of Gardenia thunbergia has antiplasmodial activity but no compounds have ever been isolated from the plant. Therefore, this study aimed to investigate the phytochemical and antiplasmodial properties of the plant. The methanol leaf extract of G. thunbergia inhibited Plasmodium falciparum at 50 µg/mL (> 80% inhibition) and was not cytotoxic against HeLa cells. Chromatographic purification of the extract afforded a new saponin and eight other known compounds. The saponin and two flavonoid glycosides displayed non-selective antiplasmodial activity at 50 µg/mL but the activities were diminished at 10 µg/mL. The presence of the isolated compounds in the leaf extract of G. thunbergia could account for the folkloric use of the plant in treating malaria. [ABSTRACT FROM AUTHOR]

The analyses of patterns of over-representation of southern African traditional medicinal plants at the genus and family level provide information about the differences in plant use among southern African countries and disease categories. 'Over-representation' refers to the phenomenon whereby the proportion of plants belonging to a taxonomic group is higher in ethnobotanical pharmacopoeia than in the total flora. This study aimed to use the Imprecise Dirichlet Model (IDM) to analyse data from ten southern African countries to establish how over-represented medicinal plant families compare with over-represented genera, how over-represented medicinal taxa differ among countries in this region of Africa, and how over-represented taxa differ among six major disease categories. Floral data for the total species composition of each country were obtained from online databases. Medicinal plant species lists were generated from published surveys, inventories, and books. IDM calculations were executed using the inverse of the cumulative beta probability density function in Microsoft Excel™. Python programming language source code was used to calculate Pearson correlation (r) values and Jaccard coefficients (J). Nine of forty-two over-represented medicinal plant families in southern Africa (group 1) do not have over-represented genera. Seven of the forty genera with the highest margins of over-representation belong to under-represented families. Nineteen of the forty-two over-represented families have margins of over-representation smaller than the cumulative margins of their over-represented genera. Groups of countries with similar overall flora (J ≥ 0.333) are Botswana and Namibia (group 2), Malawi, Mozambique, Zambia and Zimbabwe (group 3). The families and genera with the highest margins of over-representation are Loganiaceae and Albizia in group 1, Combretaceae and Vachellia in group 2, Dioscoreaceae and Senna in group 3, and Sapotaceae and Solanum in group 4 (South Africa). The families and genera with the highest margins of over-representation across disease categories are Ebenaceae and Albizia , Canellaceae and Dicoma , Combretaceae and Pterocelastrus , Ebenaceae and Bersama , Francoaceae and Erythrina , and Aristolochiaceae and Strychnos for plants used in the treatment of STIs, febrile and mosquito-vector diseases, microbial infections, pain, skin conditions, and female sexual/reproductive problems, respectively. Genus-level calculations are more efficient in generating taxonomic lists that can be used for ethnopharmacological investigations due to the exclusion of under-represented genera. Limiting the size of geographical areas from which medicinal plant lists are sampled and targeting plants used to treat specific types of disease prevents the underestimation of niche over-represented taxa. [Display omitted] [ABSTRACT FROM AUTHOR]

Chirality in drug design has been attracting wide interests and attention over the years based on its innate potentials of enhancing the selectivity and prowess of therapeutic molecules. This approach was fundamental to the recent design of two inhibitors, where (R,R)‐HEC72702 exhibited higher potency inhibition against hepatitis B virus capsid (HBVC) than (R,S)‐HEC72702. Nevertheless, the detailed molecular mechanism has remained unresolved. Here, we apply multiple computational approaches to explore, validate, and differentiate the binding modes of (R,R) and (R,S)‐HEC72702 and to explain the systematic roles mediated by chirality on the distinctive inhibition of HBVC dimer (HBVCd). Our findings revealed that chirality change from R,S to R,R engenders variations in the position of the propanoic acid group of HEC72702 toward the α5′ and C‐TER′ region of HBVCd chain B which could explain the higher inhibitory affinity of (R,R)‐HEC72702. Estimated binding free energies revealed a good correlation with bioactivity data. Moreover, analysis of energy decomposition revealed the prominent effects of van der Waals interactions in the binding process of both compounds to HBVCd. Furthermore, hierarchical clustering of residue‐based energetic contributions suggested two hot‐spot residues W125´ and F156´ play crucial roles in the systematic motions of the propanoic acid group toward chain B. [ABSTRACT FROM AUTHOR]