Sesquiterpene lactones from Vernonia cinerascens sch. bip. and their in vitro antitrypanosomal activity

In the endeavor to obtain new antitrypanosomal agents, particularly sesquiterpene lactones, from Kenyan plants of the family Asteraceae, Vernonia cinerascens Sch. Bip. was investigated. Bioactivity-guided fractionation and isolation in conjunction with LC/MS-based dereplication has led to the identification of vernodalol (1) and isolation of vernodalin (2), 11β,13-dihydrovernodalin (3), 11β,13-dihydrovernolide (4), vernolide (5), 11β,13-dihydrohydroxyvernolide (6), hydroxyvernolide (7), and a new germacrolide type sesquiterpene lactone vernocinerascolide (8) from the dichloromethane extract of V. cinerascens leaves. Compounds 3-8 were characterized by extensive analysis of their 1D and 2D NMR spectroscopic and HR/MS spectrometric data. All the compounds were evaluated for their in vitro biological activity against bloodstream forms of Trypanosoma brucei rhodesiense and for cytotoxicity against the mammalian cell line L6. Vernodalin (2) was the most active compound with an IC50 value of 0.16 µM and a selectivity index of 35. Its closely related congener 11β,13-dihydrovernodalin (3) registered an IC50 value of 1.1 µM and a selectivity index of 4.2

Response of elite Kenyan finger millet (Eleusine coracana, L. Gaertn) genotypes to Ethrel application

Finger millet is a staple food crop of many communities in Africa. The crop is highly nutritious and has incredible grain storage quality. Limited research investment in finger millet in the past has resulted in poor yields and there are currently no commercial hybrids. We investigated the response of different finger millet genotypes (Okhale-1, Gulu-E, KACCIMMI-72, IE 2872, IE 4115 and U-15) to the application of a plant growth regulator hormone (Ethrel). Six elite Kenyan finger millet varieties with contrasting agronomic traits were crossed in a 6 x 6 diallel pattern. To enhance male sterility across female parents, we subjected the plants to Ethrel at concentrations of 1,500ppm, 1,750ppm and 2,000ppm against a 0ppm check. Dwarfing of sprayed plants that resulted in less lodging and ultimately higher yields were observed among plants sprayed with Ethrel at different concentrations. Ethrel application at 2,000ppm had the most dwarfing effect on plants while spraying plants with 1,500ppm of Ethrel resulted in increased grain weight. Although our results demonstrate overall positive effect of Ethrel on finger millet production, the optimum concentrations for more efficient hybridization will still need to be determined

Preparation of sesquiterpene lactone-loaded pla nanoparticles and evaluation of their antitrypanosomal activity

Human African trypanosomiasis (HAT), also commonly known as sleeping sickness, is a neglected tropical disease affecting millions of people in poorly developed regions in sub-Saharan Africa. There is no satisfactory treatment for this infection. The investment necessary to bring new drugs to the market is a big deterrent to drug development, considering that the affected communities form a non-lucrative sector. However, natural products and many sesquiterpene lactones (STLs) in particular are very strong trypanocides. Research and applications of nano-drug delivery systems such as nanoparticles (NPs) have undergone unprecedented growth in the recent past. This is mainly due to the advantages offered by these systems, such as targeted delivery of the drug to the place of action (cell, parasite, etc), sustained release of the drug, increased bioavailability, reduced drug dosage, and reduction of undesired side effects, among others. In this study, the STLs α-santonin, arglabin, schkuhrin II, vernolepin, and eucannabinolide, all trypanocides, were loaded into polylactic acid (PLA) NPs through an emulsification-diffusion method. The NPs were stable, homogenous, and spherical in shape with a rounded knotty depression like a navel orange. The average particle sizes were 202.3, 220.3, 219.5, 216.9, and 226.4 nm for α-santonin, arglabin, schkuhrin II, vernolepin, and eucannabinolide, respectively. The NPs had encapsulation efficiencies of 94.6, 78.1, 76.8, 60.7, and 78.9% for α-santonin, arglabin, schkuhrin II, vernolepin, and eucannabinolide, respectively. The NPs loaded with arglabin, vernolepin, and eucannabinolide exhibited considerable antitrypanosomal activity against; Trypanosoma brucei rhodesiense (Tbr); with free drug equivalent IC; 50; values of 3.67, 1.11 and 3.32 µM, respectively. None of the NP formulations displayed cytotoxicity towards mammalian cells (rat skeletal myoblast cell line L6). These results provide new insights into the possibility of incorporating STLs into nanoparticles, which may provide new options for their formulation in order to develop new drugs against HAT

<b>Chemical composition and antimicrobial activity of the essential oil of <i>Satureja biflora</i> (Lamiaceae) </b>

Hydro-distilled essential oil from <i>Satureja biflora</i> (Lamiaceae) growing in Kenya was analysed by gas chromatography mass spectrometry (GC-MS) and also evaluated for antimicrobial activity. Twenty two compounds which constitute 99.29 % of the total oil were identified. The oil was dominated by monoterpenes, which accounted for 62.02 % of the oil. This monoterpene fraction was characterized by a high percentage of linalool (50.60 %) such that this <i>Satureja</i> species can be classified as the linalool chemotype. The other major monoterpenes were α-terpineol (2.80 %), β-ocimene (2.25 %), β-pinene (1.96 %) and <i>cis</i>-linalool oxide (1.91 %). Sesquiterpenes present in fairly good amounts are germacrene D (10.63 %), α-cadinol (4.53 %), β-bourbonene (2.33 %), δ-cadinene (2.19 %), τ-cadinol (2.17 %), endo-1-bourbonanol (2.14 %) and β-caryophyllene (1.98 %). Aliphatic alcohols and acids accounted for 7.23 % of the oil, of which the major one was linoleic acid (4.48 %). The oil was screened for antimicrobial activity against both gram-positive (<i>Staphylococcus aureus</i>, <i>Bacillus ssp. </i>) and gram-negative (<i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>, <i>Salmonella typhi</i>, <i>Klebsiella pheumoniae</i>, <i>Proteus mirabilis</i>) bacteria and a pathogenic fungus (<i>Candida albicans</i>). To the best of our knowledge nothing concerning the chemical composition and biological activity of the essential oil of <i>S. biflora</i> has been reported

Anti-trypanosomatid elemanolide sesquiterpene lactones from Vernonia lasiopus O. Hoffm

Sleeping sickness or human African trypanosomiasis (HAT) is a neglected tropical disease (NTD) threatening millions of peoples' lives with thousands infected. The disease is endemic in poorly developed regions of sub-Saharan Africa and is caused by the kinetoplastid "protozoan" parasite Trypanosoma brucei. The parasites are transmitted to humans through bites of infected tsetse flies of the genus Glossina. The few available drugs for treatment of this disease are highly toxic, difficult to administer, costly and unavailable to poor rural communities bearing the major burden of this infection. Therefore, the search for new efficacious, safe and affordable drugs is of high importance. Vernonia lasiopus O. Hoffm., an indigenous African plant of the Asteraceae family, has been extensively reported to be used ethno-medicinally as a treatment for malaria. Its crude extracts obtained with solvents of different polarity were screened in vitro for anti-protozoal activity and the dichloromethane extract was found to be particularly active against Trypanosoma brucei rhodesiense (IC50 = 0.17 µg/mL). Bioassay-guided chromatographic fractionation of the dichloromethane extract led to the isolation and identification of six elemanolide type sesquiterpene lactones: 8-desacylvernolide, vernolepin, vernomenin, vernodalol, vernodalin and 11,13-dihydrovernodalin. All these elemanolide sesquiterpene lactones showed in vitro anti-trypanosomal activity. They were also tested for cytotoxicity against mammalian cells (L6 cell line). Vernolepin, the main component in the extract, was also the most potent with an IC50 value of 0.05 µg/mL against T.b. rhodesiense trypomastigotes. This compound showed a selectivity index of 14.5, which makes it an interesting candidate for in vivo tests and determination of its mechanism of action

Antiprotozoal sesquiterpene lactones and other constituents from Tarchonanthus camphoratus and Schkuhria pinnata

In continuation of a search for new antiprotozoal agents from plants of the family Asteraceae, Tarchonanthus camphoratus and Schkuhria pinnata have been investigated. By following the promising in vitro activity of the dichloromethane extracts from their aerial parts, bioassay-guided chromatographic isolation yielded two known sesquiterpene lactones (1 and 2) from T. camphoratus and 20 known compounds of this type from S. pinnata. From the latter, a new eudesmanolide, (1R*,5S*,6R*,7R*,8R*,10R*)-1-hydroxy-8-[5″-hydroxy-4'-(2″-hydroxyisovaleroyloxy)tigloyloxy]-3-oxoeudesma-11(13)-en-6,12-olide (3), and two new germacranolides, 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)costunolide (14) and 1(10)-epoxy-3β-hydroxy-8β-[5'-hydroxy-4'-(2″-hydroxyisovaleroyloxy)tigloyloxy]costunolide (16), were obtained. Additionally, the flavonoid pectolinarigenin (24) and 3-hydroxy-4,5-dimethoxybenzenepropanol (25) were also isolated from S. pinnata. The compounds were characterized by analysis of 1D and 2D NMR spectroscopic and HR/MS data. In vitro antitrypanosomal activity and cytotoxicity against mammalian cells (L6 cell line) were evaluated for all the compounds. Santhemoidin A (13) and 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)costunolide (14) were the most active compounds found in this study, with IC50 values of 0.10 and 0.13 μM against Trypanosoma brucei rhodesiense trypomastigotes and selectivity indices of 20.5 and 29.7, respectively

Complementary Quantitative Structure–Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones

Three complementary quantitative structure&#8315;activity relationship (QSAR) methodologies, namely, regression modeling based on (i) &#8220;classical&#8222; molecular descriptors, (ii) 3D pharmacophore features, and (iii) 2D molecular holograms (HQSAR) were employed on the antitrypanosomal activity of sesquiterpene lactones (STLs) toward Trypanosoma brucei rhodesiense (Tbr), the causative agent of the East African form of human African trypanosomiasis. In this study, an extension of a previous QSAR study on 69 STLs, models for a much larger and more diverse set of such natural products, now comprising 130 STLs of various structural subclasses, were established. The extended data set comprises a variety of STLs isolated and tested for antitrypanosomal activity within our group and is furthermore enhanced by 12 compounds obtained from literature, which have been tested in the same laboratory under identical conditions. Detailed QSAR analyses yielded models with comparable and good internal and external predictive ability. For a set of compounds as chemically diverse as the one under study, the models exhibited good coefficients of determination (R2) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q2 values ranging from 0.62 to 0.72) and external validation coefficients (P2 values ranging from 0.54 to 0.73). The contributions of the various tested descriptors to the generated models are in good agreement with the results of previous QSAR studies and corroborate the fact that the antitrypanosomal activity of STLs is very much dependent on the presence and relative position of reactive enone groups within the molecular structure but is influenced by their hydrophilic/hydrophobic properties and molecular shape