Voulkensin C-E, new 11-oxocassane-type diterpenoids and a steroid glycoside from Caesalpinia volkensii stem bark and their antiplasmodial activities.

A bioassay guided isolation of potential antimalarial molecules from the stem bark of Caesalpinia volkensii Harms (Fabaceae) achieved three new 11-oxocassane-type diterpenoids named voulkensin C (1), D (2) and E (3) together with one steroid glycoside named 3-O-[ß-glucopyranosyl(1→2)-O-ß-xylopyranosyl]-stigmasterol (4) and seven other known compounds including stigmasterol (5), ß-sitosterol (6), oleanolic acid (7), 3-ß-acetoxyolean-12-en-28-methyl ester (8), voucap-5-ol (9), caesadekarin C (10), deoxycaesaldekarin C (11). The structures of the new compounds were determined on the basis of extensive spectroscopic data (IR, MS, (1)H and (13)C NMR and 2D NMR) analyses. The polar extracts revealed moderate to good antiplasmodial activities against chloquine-sensitive (D6) and -resistant strains (W2) of Plasmodium falciparum. Whereas the pure isolates exhibited limited to moderate antiplasmodial activities with compound 4 showing the highest antiplasmodial activities (IC50 values of 4.44±0.88 and 2.74±1.10µM against D6 and W2 strains, respectively). These results suggest a possible contribution of phytochemicals from C. volkensii stem bark towards inhibition of plasmodial parasites' growth hence potential antimalarial.

Phytoecdysteroids from the stem bark of Vitex doniana and their anti-inflammatory effects.

With reference to the ethnopharmacological significance of Vitex doniana Sweet (Lamiaceae) leaves in the treatment of stomach and rheumatic pains as well as inflammatory disorders, biological studies on its stem bark extracts have also reported anti-inflammatory and analgesic activities, with no attempt to identify the active components. Chromatographic and spectroscopic procedures identified three new phytoecdysteroids: 21-hydroxyshidasterone (1), 11ß-hydroxy-20-deoxyshidasterone (2), and 2,3-acetonide-24-hydroxyecdysone (3) from the stem bark methanol extracts along with known ecdysteroids shidasterone (4), ajugasterone C (5), 24-hydroxyecdysone (6), and 11ß,24-hydroxyecdysone (7). The compounds (1-7) showed significant (p ≤ 0.05) inhibitory effect at 100 mg/kg dose on rat paw oedema development due to carrageenan-induced inflammation in Sprague Dawley rats. These results suggest a possible contribution of ecdysteroids to the anti-inflammatory effect of some V. doniana stem bark extracts.

Inhibition Kinetics and Theoretical Studies on Zanthoxylum chalybeum Engl. Dual Inhibitors of α-Glucosidase and α-Amylase.

Compounds from Zanthoxylum chalybeum Engl. were previously reported for inhibitory activities of amylase and glucosidase enzymatic action on starch as a preliminary study toward the establishment of a management strategy against postprandial hyperglycemia, however, the inhibitory kinetics and molecular interaction of these compounds were never established. A study was thus designed to establish the inhibitory kinetics and in silico molecular interaction of α-glucosidase and α-amylase with Z. chalybeum metabolites based on Lineweaver-Burk/Dixon plot analyses and using Molecular Operating Environment (MOE) software, respectively. Skimmianine (5), Norchelerythrine (6), 6-Acetonyldihydrochelerythrine (7), and 6-Hydroxy-N-methyldecarine (8) alkaloids showed mixed inhibition against both α-glucosidase and α-amylase with comparable Ki to the reference acarbose (p > 0.05) on amylase but significantly higher activity than acarbose on α-glucosidase. One phenolic 2,3-Epoxy-6,7-methylenedioxyconiferol (10) showed a competitive mode of inhibition both on amylase and glucosidase which were comparable (p > 0.05) to the activity of acarbose. The other compounds analyzed and displayed varied modes of inhibition between noncompetitive and uncompetitive with moderate inhibition constants included chaylbemide A (1), chalybeate B (2) and chalybemide C (3), fagaramide (4), ailanthoidol (9), and sesame (11). The important residues of the proteins α-glucosidase and α-amylase were found to have exceptional binding affinities and significant interactions through molecular docking studies. The binding affinities were observed in the range of -9.4 to -13.8 and -8.0 to -12.6 relative to the acarbose affinities at -17.6 and -20.5 kcal/mol on α-amylase and α-glucosidase residue, respectively. H-bonding, π-H, and ionic interactions were noted on variable amino acid residues on both enzymes. The study thus provides the basic information validating the application of extracts of Z. chalybeum in the management of postprandial hyperglycemia. Additionally, the molecular binding mechanism discovered in this study could be useful for optimizing and designing new molecular analogs as pharmacological agents against diabetes.

Monoaminergic system involvement in the antidepressant-like and anxiolytic-like properties of novel ß-dihydroagarofuran sesquiterpene alkaloid and triterpenes isolated from Gymnosporia heterophylla aerial parts in mice.

Gymnosporia heterophylla (synonym Maytenus) is widely used in folk medicine for the treatment of various illness including neurological diseases. This study presents the antidepressant-like and anxiolytic-like effects of novel bioactive constituents; 3,4-seco-1-hydroxy-21-oxoolean-3,11-olide (A2), 1ß,2ß-diacetoxy-9ß-benzoyloxy-6α-nicotinoyloxy-ß-dihydroagarofuran (A5) as well as known 3-acetoxy-1ß-hydroxyLupe-20(29)-ene (selective COX-2; A4) from the aerial parts of G. heterophylla. The antidepressant-like effect was studied using the forced swim test (FST) while the elevated plus maze test (EPMT) and open field test (OFT) were employed for anxiolytic-like effect. Acute treatment with A4 and A5 (0.5, 5 or 10 mg/kg) significantly reduced the duration of immobility and immobile episodes with prolongation of immobility latency in the FST with peak effects observed at 10 and 0.5 mg/kg, respectively. Moreover, antidepressant-like effect of A4 and A5 were relatively better than that of fluoxetine. Conversely, the pretreatment of mice with prazosin (1 mg/kg, α1-adrenoceptor antagonist), yohimbine (1 mg/kg; α2-adrenoceptor antagonist), or sulpiride (50 mg/kg; dopamine D2-receptor antagonist) reversed antidepressant-like effect of A4 and A5 but not WAY 100635 (10 mg/kg, i.p., selective 5-HT1A receptor antagonist), GR 127935 (5 mg/kg, i.p., selective 5-HT1B receptor antagonist), metergoline (4 mg/kg, i.p, non-selective 5-HT2 receptor antagonist), ketanserin (5 mg/kg, i.p., a selective 5-HT2A receptor antagonist) or p-chlorophenylalanine (pCPA) (100 mg/kg, i.p., tryptophan hydroxylase inhibitor) in the FST. Interestingly, A2, A4 and A5 significantly increased the time spent in the open arms of the EPM suggestive of anxiolytic-like action. Findings from this study showed that the novel ß-dihydroagarofuran sesquiterpene alkaloid and triterpenes possesses antidepressant-like and anxiolytic-like effects through enhancement of monoaminergic signaling.

α-Amylase and α-glucosidase inhibitors from Zanthoxylum chalybeum Engl. root bark.

A systematic analysis of the root bark of Zanthoxylum chalybeum was conducted to establish the antidiabetic potential of isolated compounds based on its ethnomedicinal use to manage diabetes. Chromatographic separation of alkaloid extracts led to isolation of three undescribed amides, chaylbemide A (1), chalybemide B (2) and chalybemide C (3) alongside the known fagaramide (4); four known benzophenanthridine alkaloids skimmianine (5), norchelerythrine (6), 6-acetonyldihydrochelerythrine (7) and 6-hydroxy-N-methyl decarine (8). The alkaloid free extracts yielded three known lignans, ailanthoidol (9), 2,3-epoxy-6,7-methylenedioxy coniferyl alcohol (10), sesamine (11), together with five known triterpenoids, lupeol (12), lupanone (13), 3α,20-dihydroxy-28-lupanoic acid (14), 20-hydroxy-3-oxo-28-lupanoic acid (15) and 3α,20,28-trihydroxylupane (16). The structures of the compounds were established based on 1D and 2D NMR spectroscopic and mass spectrometric experiments. Compounds 1-8 displayed inhibitory activities against both α-amylase and α-glycosidase in the range of IC50 = 43.22-49.36 µM which showed no significant (P > 0.05) difference to the positive control acarbose (IC50 = 42.67; 44.88 µM). The results confirmed anti-hyperglycemic potential of alkaloids from Z. chalybeum which lends credence to its use towards management of diabetes susceptibilities.

Cyclooxygenase inhibitory compounds from Gymnosporia heterophylla aerial parts.

Gymnosporia heterophylla (Celastraceae) is an African medicinal plants used to treat painful and inflammatory diseases with partial scientific validation. Solvent extractions followed by repeated chromatographic purification of the G. heterophylla aerial parts led to the isolation of one new ß-dihydroagarofuran sesquiterpene alkaloid (1), and two triterpenes (2-3). In addition, eight known compounds including one ß-dihydroagarofuran sesquiterpene alkaloid (4), and six triterpenes (5-10) were isolated. All structures were determined through extensive analysis of the NMR an MS data as well as by comparison with literature data. These compounds were evaluated for the anti-inflammatory activities against COX-1 and -2 inhibitory potentials. Most of the compound isolated showed non selective COX inhibitions except for 3-Acetoxy-1ß-hydroxyLupe-20(29)-ene (5), Lup-20(29)-ene-1ß,3ß-diol (6) which showed COX-2 selective inhibition at 0.54 (1.85), and 0.45 (2.22) IC50, in mM (Selective Index), respectively. The results confirmed the presence of anti-inflammatory compounds in G. heterophylla which are important indicators for development of complementary medicine for inflammatory reactions; however, few could be useful as selective COX-2 inhibitor.

Mechanisms of analgesic and anti-inflammatory properties of Annona muricata Linn. (Annonaceae) fruit extract in rodents.

Unripe fruit of Annona muricata Linn. (Annonaceae) (soursop) is used in traditional African medicine for the treatment of neuralgia, rheumatism, and arthritic pain. This study sought to investigate the analgesic and anti-inflammatory effects of lyophilized fruit extract of Annona muricata (AM) in rodents. The analgesic activity was evaluated using the mouse writhing, formalin, and hot-plate tests while the anti-inflammatory action was investigated using the carrageenan-induced rat paw edema and xylene-induced ear edema tests. Pretreatment with AM (50, 100, and 200 mg/kg, p.o.) produced dose-dependent (P<.001) inhibition of writhes and formalin-induced pain in the late phase. AM and morphine produced time-course increase in pain threshold in hot-plate test. However, the analgesic effect elicited by AM was reversed (P<.05) by naloxone pretreatment. Similarly, the time-dependent increase in paw circumference induced by carrageenan was inhibited by AM treatment with peak effect (0.23±0.10 cm; P<.001, 200 mg/kg; 6 h), which was comparatively similar to that of diclofenac treated. Further, the xylene-induced ear edema was significantly reduced by AM (50 or 100 mg/kg) pretreatment; however, the anti-inflammatory effect elicited by AM was prevented by pretreatment of mice with N(G)-nitro-l-arginine (20 mg/kg, i.p., nitric-oxide synthase inhibitor) 15 min before AM (200 mg/kg, p.o.). The in vitro cyclooxygenase assay also showed that AM produced concentration-dependent inhibition of both cyclooxygenase (COX)-1 and COX-2 activity by 39.44%±0.05% and 55.71%±0.12%, respectively, at 100 µg/mL. In conclusion, A. muricata possesses analgesic effect through interaction with opioidergic pathway and anti-inflammatory property through inhibition of chemical mediators of inflammation.

Potential of novel phytoecdysteroids isolated from Vitex doniana in the treatment depression: involvement of monoaminergic systems.

Vitex doniana Sweet (Verbanaceae) is used in traditional African medicine for the treatment of neurological disorders including depression. In our previous studies, three new phytoecdysteroids were isolated from methanol stem bark extract of V. doniana (VD) (11ß-hydroxy-20-deoxyshidasterone, 21-hydroxyshidasterone, and 2,3-acetonide-24-hydroxyecdysone) along with known ecdysteroids. This study was designed to investigate antidepressant-like effect of VD and the isolated phytoecdysteroids in behavioral models of despair, forced-swim test (FST) and tail-suspension test (TST) in mice. VD (100 and 200mg/kg, p.o.) treatment reduced (P<0.05) the duration of immobility in both tests without affecting the locomotor activity and exploratory behavior as observed in the open field test. Similarly, 21-hydroxyshidasterone, 11ß-hydroxy-20-deoxyshidasterone, ajugasterone and 24-hydroxyecdysone acute oral treatments significantly reduced immobility time with peak effect at 10mg/kg, which was similar to the effect of conventional antidepressants (imipramine and fluoxetine) in the FST. Conversely, pretreatment of mice with yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist), ketanserin (5mg/kg, i.p., 5-HT2A/2C receptor antagonist) or sulpiride (dopamine D2 receptor antagonist) prevented the antidepressant-like effect of 21-hydroxyshidasterone while the effects of 11ß-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone were blocked by yohimbine or ketanserin in the FST. Moreover, the anti-immobility effect elicited by ajugasterone was prevented by prazosin (62.5µg/kg, i.p., α1-adrenoceptor antagonist) pretreatment. Our findings demonstrated that V. doniana and its phytoecdysteroids constituents elicited antidepressant-like effect in behavioral paradigm of despair. Furthermore, 21-hydroxyshidasterone produces its antidepressant-like effect through interaction with α2-adrenoceptor, 5-HT2A/2C receptor and dopamine D2-receptors but 11ß-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone effects depend on interaction with α2-adrenoceptor and 5-HT2A/2C receptors while ajugasterone produces its action through interaction with post-synaptic α1-adrenoceptors. Thus, phytoecdysteroids could play a pivotal role in the treatment of major depression.

New ceramide from the aerial part of Tinospora oblongifolia with cytotoxic activities.

A new ceramide, 2,3-dihydroxy-N-[(2S,3S,4R)-1,3,4-trihydroxyicosan-2-yl[tetracosanamide (1) along with four known compounds: 2-(4'-hydroxyphenyl)-ethyl lignocerate (2), docosyl-3,4-dihydroxy-trans-cinnamate (3), ß-sitosterol (4) and ß-sitosterol glycoside (5) were isolated from Tinospora oblongifolia (Menispermaceae). Their structures were determined on the basis of spectroscopic methods, mass spectrometry analysis as well as chemical transformation and by comparing their physical and spectral data with those reported in the literature. Compound 1 exhibited strong cytotoxic activity against KB cells with IC50 = 3.4 µM although less than that of camptothecin IC50 = 0.3 µM (positive control).

Antinociceptive and antiplasmodial activities of cassane furanoditerpenes from Caesalpinia volkensii H. root bark.

The chloroform and ethyl acetate extract (100mg/kg) of Caesalpinia volkensii H. exhibited significant (P ≤ 0.05) antinociceptive activities using hot plate and writhing tests in mice while the later showed antiplasmodial activity (IC(50) 0.23 ± 0.07 and 4.39 ± 2.49 µg/ml) against chloroquine sensitive (D6) and chloroquine-resistant (W2), respectively. Two new furanoditerpenes [rel. 1ß,5α-dihydroxyvoucapane (1) and rel. 1ß,6ß-dihydroxyvoucapane; 19ß-methyl ester (2)] together with seven known compounds [voucapane (3), voucapan-5-ol (4), deoxycaesaldekarin C (5), caesaldekarin C (6), 5-hydroxyvinhaticoic acid (7), triacontanyl-(E)-ferulate (8), triacontanyl-(E)-caffaete (9) and 30'-hydroxytriacontanyl-(E)-ferulate (10)] were isolated from the two extracts. The administration of 3, 4, 5 and 6 (100mg/kg i.p) caused a significant (P ≤ 0.05) reduction in the number of writhing episodes induced by acetic acid and (P ≤ 0.01) increased pain latency threshold in hot-plate test compared to control. However, the pure compounds indicated relatively (P ≤ 0.05) low antiplasmodial activity. The phytochemical constituents from the root bark of C. volkensii had better analgesic properties than antimalarial properties, justifying the use of the plant root bark as a remedy for pain.