Genus Monanthotaxis: a review on distribution, ethnomedicinal uses and phytochemistry.

This article reviews the geographical distribution, ethnomedicinal applications, and phytochemistry of the genus Monanthotaxis Baill, tribe Uvariae of the family Annonaceae. The reviewed works of literature were collected from various electronic databases including Google Scholar, PubMed, Science Direct, The International Plant Names Index (IPNI), and Research Gate. During this review, ninety-eight species of the genus Monanthotaxis were found to be widely distributed in tropical Africa. Some of those species are used in folkloric medicine by various communities to manage diseases and disease conditions such as fever, vomiting, headache, stomach-ache, malaria, helminthiasis, and hysteria. In the past 44 years (1979 to 2023), one hundred and nineteen secondary metabolites with different biomedical potentials have been reported from this genus. The reported compounds are categorised into flavonoids, alkaloids, terpenoids, polyoxygenated cyclohexane, and cyclohexene derivatives, benzyl derivatives, cinnamic acid derivatives, and stilbenoids. Most of the reported compounds showed an array of bioactivities corroborating the use of some members of the genus in folkloric medicine.

Crotofolane Diterpenoids and Other Constituents Isolated from Croton kilwae.

Six new crotofolane diterpenoids (1-6) and 13 known compounds (7-19) were isolated from the MeOH-CH2Cl2 (1:1, v/v) extracts of the leaves and stem bark of Croton kilwae. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and mass spectrometric data. The structure of crotokilwaepoxide A (1) was confirmed by single-crystal X-ray diffraction, allowing for the determination of its absolute configuration. The crude extracts and the isolated compounds were investigated for antiviral activity against respiratory syncytial virus (RSV) and human rhinovirus type-2 (HRV-2) in HEp-2 and HeLa cells, respectively, for antibacterial activity against the Gram-positive Bacillus subtilis and the Gram-negative Escherichia coli, and for antimalarial activity against the Plasmodium falciparum Dd2 strain. ent-3ß,19-Dihydroxykaur-16-ene (7) and ayanin (16) displayed anti-RSV activities with IC50 values of 10.2 and 6.1 µM, respectively, while exhibiting only modest cytotoxic effects on HEp-2 cells that resulted in selectivity indices of 4.9 and 16.4. Compounds 2 and 5 exhibited modest anti-HRV-2 activity (IC50 of 44.6 µM for both compounds), while compound 16 inhibited HRV-2 with an IC50 value of 1.8 µM. Compounds 1-3 showed promising antiplasmodial activities (80-100% inhibition) at a 50 µM concentration.

Neuroprotective potential of cinnamoyl derivatives against Parkinson's disease indicators in Drosophila melanogaster and in silico models.

Parkinson's disease (PD) is a movement disorder resulting from the loss of dopaminergic neurons over time. While there is no cure for PD, available conventional therapies aid to manage the motor symptoms. Natural products (NPs) derived from plants are among the most potent alternative therapies for PD. This study explored the neuroprotective potential of selected cinnamoyl derivatives namely toussaintine A (1), E-toussaintine E (2), asperphenamate (3) and julocrotine (4) against PD indicators using rotenone-challenged Drosophila melanogaster and in silico models. The compounds were first assessed for their toxicity preceding treatment experiments. Adult flies (aged 1-4 days) were exposed to varying concentrations of the compounds for 7 days. During the experiment, the mortality of flies was observed, and the lethal concentration (LC50) of each tested compound was determined. The LC50 values were found to be 50.1, 55.6, 513.5, and 101.0 µM for compounds 1, 2, 3, and 4, respectively. For seven days, we exposed flies to 500 µM of rotenone and co-fed with a chosen dose of 40 µM of each test compound in the diet. Using a negative geotaxis test, rotenone-challenged flies exhibited compromised climbing ability in comparison to control flies, the condition that was reversed by the action of studied compounds. Rotenone exposure also elevated malondialdehyde levels in the brain tissues, as measured by lipid peroxidation, when compared to control flies. In flies exposed to rotenone and co-fed with the compounds, this effect was lessened. In flies exposed to rotenone, mRNA levels of antioxidant enzymes such as superoxide dismutase and catalase were raised but were normalized in flies treated with the investigated compounds. Moreover, in-silico studies examined the inhibitory ability of compounds 1-4 against selected PD molecular targets, revealing the strong power of toussaintine A (1) against Adenosine receptor 2 (A2AR) and monoamine oxidase B. Thus, our findings suggest that cinnamoyl derivatives have neuroprotective potential via reducing the oxidative burden and improving locomotor ability after toxin invectives. In particular, compound 1 at lower doses can simultaneously be a potential inhibitor of A2AR and an anti-oxidative mediator in the development of anti-PD agents.

Modified ent-Abietane Diterpenoids from the Leaves of Suregada zanzibariensis.

The leaf extract of Suregada zanzibariensis gave two new modified ent-abietane diterpenoids, zanzibariolides A (1) and B (2), and two known triterpenoids, simiarenol (3) and ß-amyrin (4). The structures of the isolated compounds were elucidated based on NMR and MS data analysis. Single-crystal X-ray diffraction was used to establish the absolute configurations of compounds 1 and 2. The crude leaf extract inhibited the infectivity of herpes simplex virus 2 (HSV-2, IC50 11.5 µg/mL) and showed toxicity on African green monkey kidney (GMK AH1) cells at CC50 52 µg/mL. The isolated compounds 1-3 showed no anti-HSV-2 activity and exhibited insignificant toxicity against GMK AH1 cells at ≥100 µM.

Hydrophobic π-π stacking interactions and hydrogen bonds drive self-aggregation of luteolin in water.

Luteolin is a flavonoid obtained from different plant species. It is known for its versatile biological activities. However, the beneficial effects of luteolin have been limited to small concentrations as a result of poor water solubility. This study aimed at investigating the hydrophobic interaction and hydration of luteolin towards the improvement of its solubility when used as a drug. We report the aggregation properties of luteolin in water by varying the number of monomers using atomistic molecular dynamics simulation. Results show that the equilibrium structure of luteolin occurs in an aggregated state with different structural arrangements. As the monomers size increase, the antiparallel flipped conformation dominates over T-shaped antiparallel, T-shaped parallel, and antiparallel conformations. The formation of intramolecular hydrogen bonding of 0.19 nm between the keto-enol groups results in hydrophobic characteristics. A larger cluster exhibits slow hydrogen bond dynamics for luteolin-luteolin than luteolin-water interaction. Water structure at large cluster size exhibited slow dynamics and low self-diffusion of luteolin. The existence of hydrophobic π-π and hydrogen bonds between luteolin molecules drives strong self-aggregation resulting in poor water solubility. Breakage of these established interactions would result in increased solubility of luteolin in water.

Polyoxygenated cyclohexene derivatives and flavonoids from the leaves of Uvaria pandensis.

Three new oxygenated cyclohexene derivatives, pandensenol D - F (1-3), two new flavanoids, pandensone A and B (4-5), and seven known compounds (6-12) were isolated from the methanol extract of the leaves of Uvaria pandensis Verdc. (Annonaceae). The structures were characterized by NMR spectroscopic and mass spectrometric analyses. The isolated metabolites were evaluated for their antibacterial activity against the Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis, the Gram-negative bacteria Enterococcus raffinosus, Escherichia coli, Paraburkholderia caledonica, Pectobacterium carotovorum and Pseudomonas putida, and for cytotoxicity against the MCF-7 human breast cancer cell line. Out of the tested compounds, pandensenol D (1) and (6',7'-dihydro-8'α,9'ß-dihydroxy)-3-farnesylindole (12) showed weak activity, whereas (8'α,9'ß-dihydroxy)-3-farnesylindole (11) strong activity against B. subtilis. Four of the isolated compounds (1, 4, 11 and 12) showed moderate cytotoxicity against MCF-7 breast cancer cells (EC50 > 100 µM).

Oxygenated Cyclohexene Derivatives from the Stem and Root Barks of Uvaria pandensis.

Five new cyclohexene derivatives, dipandensin A and B (1 and 2) and pandensenols A-C (3-5), and 16 known secondary metabolites (6-21) were isolated from the methanol-soluble extracts of the stem and root barks of Uvaria pandensis. The structures were characterized by NMR spectroscopic and mass spectrometric analyses, and that of 6-methoxyzeylenol (6) was further confirmed by single-crystal X-ray crystallography, which also established its absolute configuration. The isolated metabolites were evaluated for antibacterial activity against the Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis and the Gram-negative bacteria Enterococcus raffinosus, Escherichia coli, Paraburkholderia caledonica, Pectobacterium carotovorum, and Pseudomonas putida, as well as for cytotoxicity against the MCF-7 human breast cancer cell line. A mixture of uvaretin (20) and isouvaretin (21) exhibited significant antibacterial activity against B. subtilis (EC50 8.7 µM) and S. epidermidis (IC50 7.9 µM). (8'α,9'ß-Dihydroxy)-3-farnesylindole (12) showed strong inhibitory activity (EC50 9.8 µM) against B. subtilis, comparable to the clinical reference ampicillin (EC50 17.9 µM). None of the compounds showed relevant cytotoxicity against the MCF-7 human breast cancer cell line.

Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics.

Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.

Solvent effects on host-guest residence time and kinetics: further insights from metadynamics simulation of Toussaintine-A unbiding from chitosan nanoparticle.

Solvents play an important role in host-guest intermolecular interactions. The kinetics and residence time of Toussaintine-A (TouA) unbinding from chitosan was investigated by means of well-tempered metadynamics and thermodynamic integration using two solvents, polar aprotic (DMSO), and polar protic (water). The kinetic rates were found to be strongly dependent on the solvent polarity; hence, the unbinding rate proceeded much faster in DMSO compared to water. DMSO tends to participate less in a chemical reaction by weakening the intermolecular interaction between chitosan and TouA due to lack of acidic hydrogen resulting in a reduction of the transition state. On the other hand, water, which ought to donate hydrogen atoms, sustains a strong interaction and hence large barrier heights. Consequently, this reduces the unbinding rate and increases the residence time. Binding free energy from thermodynamic integration suggests a thermodynamic stable chitosan-TouA complex in water than in DMSO. Graphical abstract.

Draft Genome Sequence of Limnospira sp. Strain BM01, Isolated from a Hypersaline Lake of the Momela Ecosystem in Tanzania.

The genus Limnospira includes cyanobacterial species used for industrial production of dietary supplements and nutraceutical agents. The metagenome-assembled genome of Limnospira sp. strain BM01 from Big Momela Lake, Tanzania, was 6,228,312 bp long with a GC content of 44.8% and carried 4,921 proteins and 52 RNA genes, including 6 rRNA genes.

Ensemble-based screening of natural products and FDA-approved drugs identified potent inhibitors of SARS-CoV-2 that work with two distinct mechanisms.

The recent outbreak of SARS-CoV-2 is responsible for high morbidity and mortality rate across the globe. This requires an urgent identification of drugs and other interventions to overcome this pandemic. Computational drug repurposing represents an alternative approach to provide a more effective approach in search for COVID-19 drugs. Selected natural product known to have antiviral activities were screened, and based on their hits; a similarity search with FDA approved drugs was performed using computational methods. Obtained drugs from similarity search were assessed for their stability and inhibition against SARS-CoV-2 targets. Diosmin (DB08995) was found to be a promising drug that works with two distinct mechanisms, preventing viral replication and viral fusion into the host cell. Isoquercetin (DB12665) and rutin (DB01698) work by inhibiting viral replication and preventing cell entry, respectively. Our analysis based on molecular dynamics simulation and MM-PBSA binding free energy calculation suggests that diosmin, isoquercetin, rutin and other similar flavone glycosides could serve as SARS-CoV-2 inhibitor, hence an alternative solution to treat COVID-19 upon further clinical validation.

Antibacterial and cytotoxic biflavonoids from the root bark of Ochna kirkii.

The new isoflavonoid kirkinone A (1) and biflavonoid kirkinone B (2) along with six known compounds (3-8) were isolated from the methanolic extract of the root bark of Ochna kirkii. The compounds were identified by NMR spectroscopic and mass spectrometric analyses. Out of the eight isolated natural products, calodenin B (4) and lophirone A (6) showed significant antibacterial activity against the Gram-positive bacterium Bacillus subtilis with MIC values of 2.2 and 28 µM, and cytotoxicity against the MCF-7 human breast cancer cell line with EC50 values of 219.3 and 19.2 µM, respectively. The methanolic crude extract of the root bark exhibited cytotoxicity at EC50 8.4 µg/mL. The isolated secondary metabolites and the crude extract were generally inactive against the Gram-negative Escherichia coli (MIC ≥400 µg/mL). Isolation of biflavonoids and related secondary metabolites from O. kirkii demonstrates their chemotaxonomic significance to the genus Ochna and to other members of the family Ochnaceae.

Biflavanones, Chalconoids, and Flavonoid Analogues from the Stem Bark of Ochna holstii.

Two new biflavanones (1 and 2), three new bichalconoids (3-5), and 11 known flavonoid analogues (6-16) were isolated from the stem bark extract (CH3OH-CH2Cl2, 7:3, v/v) of Ochna holstii. The structures of the isolated metabolites were elucidated by NMR spectroscopic and mass spectrometric analyses. The crude extract and the isolated metabolites were evaluated for antibacterial activity against Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) as well as for cytotoxicity against the MCF-7 human breast cancer cell line. The crude extract and holstiinone A (1) exhibited moderate antibacterial activity against B. subtilis with MIC values of 9.1 µg/mL and 14 µM, respectively. The crude extract and lophirone F (14) showed cytotoxicity against MCF-7 with EC50 values of 11 µg/mL and 24 µM, respectively. The other isolated metabolites showed no significant antibacterial activities (MIC > 250 µM) and cytotoxicities (EC50 ≥ 350 µM).

A new indole alkaloid and other constituents from Monodora minor and Uvaria tanzaniae: their antitrypanosomal and antiplasmodial evaluation.

Phytochemical investigation of the methanolic extract of Monodora minor Engl. & Diels (Annonaceae) stem bark yielded a new indole (E)-4-(1H-indol-5-yl)-but-3-en-2-one (1), a known indole 5-formyl-1H-indole (2) and an ubiquitous steroid sitosterol (3). The investigations of the methanolic extract of Uvaria tanzaniae Verdc. (Annonaceae) root bark yielded two previously reported C-benzylated dihydrochalcones namely uvaretin (4) and diuvaretin (5). Structures of the isolated compounds were elucidated based on NMR spectroscopy and high resolution electron ionization mass spectrometry (HR-EI-MS) data. All compounds were tested against Trypanosoma brucei brucei and Plasmodium falciparum. At a single concentration (20 µM) in the antitrypanosomal and antiplasmodial assays, compound 4 exhibited remarkable activities against T. brucei brucei and P. falciparum with percentage inhibition of 97.3% and 83.0% respectively, whereas compounds 1, 2, 3 and 5 were inactive. In a dose response antiplasmodial assay compound 4 exhibited moderate activity against P. falciparum with an IC50 value of 7.20 µM.

Ameliorative effects of flavonoids and polyketides on the rotenone induced Drosophila model of Parkinson's disease.

Parkinson's disease (PD) is a movement disorder associated with the progressive loss of dopaminergic neurons (DA). PD treatment remains unsatisfactory as the current synthetic drugs in clinical use relies on managing only motor symptoms. This study investigated antioxidant potentials of selected compounds namely, 5,6,7,4'-tetramethoxyflavone (1), 6-hydroxy-2,3,4,4'-tetramethoxychalcone (2), 6-methoxyhamiltone A (3), diosquinone (4) and toussantine D (5) against rotenone (6) induced PD in Drosophila melanogaster. Toxicity of these compounds was conducted by monitoring flies' survival for seven days and determining the lethal concentrations (LC50). Whereas compound 1 had LC50 value of 91.3 µM within three days, compounds 2, 3, 4, and 5 had LC50 values of 87.2, 58.0, 64.0 and > 1000 µM, respectively on the seventh day of the experiment. We exposed flies (1-4 days old) to 500 µM rotenone and co-treated with different doses of the test compounds in the diet for seven days at final concentrations of 11.0, 43.6 and 87.2 µM for compounds 2 and 3. The concentrations used for compound 4 were 8.0, 32.0 and 64.0 µM, while 250, 500 and 1000 µM were used for compound 5. Rotenone fed flies showed impaired climbing ability compared to control flies, the phenotype that was rescued by the treatment of tested phytochemicals. Rotenone toxicity also increased malondialdehyde levels assayed by lipid peroxidation in the brain tissues relative to control flies. This effect was reduced in flies exposed to rotenone and co-treated with the phytochemicals. Moreover, expression levels of mRNA of antioxidant enzymes; superoxide dismutase and catalase were elevated in flies exposed to rotenone and normalized in flies that were co-treated with tested compounds. Besides compound 1, this study provides overall evidence that the tested flavonoids and polyketides ameliorated the rotenone provoked neurotoxicity in D. melanogaster by battling the induced oxidative stress in brain cells including DA neurons and hence rescue the locomotor behaviour deficits.

Ent-clerodane and ent-trachylobane diterpenoids from Croton dictyophlebodes.

The stem bark and root bark extracts of Croton dictyophlebodes (Euphorbiaceae) yielded seven undescribed ent-clerodanes: 15,16-epoxy-17,12(S)-olide-ent-cleroda-1,3,13(16),14-tetraen-18-oic acid methyl ester (crotodictyo A), 3ß,4ß:15,16-diepoxy-ent-cleroda-13(16),14-dien-20-al (crotodictyo B), 3ß,4ß:15,16-diepoxy-ent-cleroda-13(16),14-dien-19,20-dioic acid (crotodictyo C), 3ß,4ß:15,16-diepoxy-ent-cleroda-13(16),14-dien-20,19-olide (crotodictyo D), 3ß,4ß:15,16-diepoxy-20,12(R)-olide ent-cleroda-13(16),14-dien-19-oic acid methyl ester (crotodictyo E), 15,16-epoxy-ent-cleroda-3,13(16),14-trien-12-oxo-18-oic acid (crotodictyo F) and 15,16-epoxy-ent-cleroda-1,3,13(16),14-tetraen-12-oxo-18-oic acid (crotodictyo G), in addition to 15,16-epoxy- ent-cleroda-3,13(16),14-trien-12-oxo-18-oic acid methyl ester (crotodictyo H), reported previously as a synthetic derivative, and acetyl aleuritolic acid. The root extract yielded two ent-trachylobanes, ent-trachylobane-18,19-diol, the undescribed ent-trachylobane-2α,19-diol, along with ent-kaur-16-en-19-oic acid and 2-methoxybenzyl benzoate. Compounds were evaluated against the NCI 60 panel of human tumour cell lines at a single dose of 10-5 M, but showed no significant activity.

Secoiridoids and Iridoids from Morinda asteroscepa.

The new 2,3-secoiridoids morisecoiridoic acids A (1) and B (2), the new iridoid 8-acetoxyepishanzilactone (3), and four additional known iridoids (4-7) were isolated from the leaf and stem bark methanol extracts of Morinda asteroscepa using chromatographic methods. The structure of shanzilactone (4) was revised. The purified metabolites were identified using NMR spectroscopic and mass spectrometric techniques, with the absolute configuration of 1 having been established by single-crystal X-ray diffraction analysis. The crude leaf extract (10 µg/mL) and compounds 1-3 and 5 (10 µM) showed mild antiplasmodial activities against the chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7).

A Meroisoprenoid, Heptenolides, and C-Benzylated Flavonoids from Sphaerocoryne gracilis ssp. gracilis.

A new meroisoprenoid (1), two heptenolides (2 and 3), two C-benzylated flavonoids (4 and 5), and 11 known compounds (6-16) were isolated from leaf, stem bark, and root bark extracts of Sphaerocoryne gracilis ssp. gracilis by chromatographic separation. The structures of the new metabolites 1-5 were established by NMR, IR, and UV spectroscopic and mass spectrometric data analysis. (Z)-Sphaerodiol (7), (Z)-acetylmelodorinol (8), 7-hydroxy-6-hydromelodienone (10), and dichamanetin (15) inhibited the proliferation of Plasmodium falciparum (3D7, Dd2) with IC50 values of 1.4-10.5 µM, although these compounds also showed cytotoxicity against human embryonic kidney HEK-293 cells. None of the compounds exhibited significant disruption in protein translation when assayed in vitro.

Oxygenated Cyclohexene Derivatives and Other Constituents from the Roots of Monanthotaxis trichocarpa.

Three new oxygenated cyclohexene derivatives, trichocarpeols A (1), B (2), and C (3), along with nine known secondary metabolites, were isolated from the methanolic root extract of Monanthotaxis trichocarpa. They were identified by NMR spectroscopic and mass spectrometric analyses, and the structure of trichocarpeol A (1) was confirmed by single-crystal X-ray diffraction. Out of the 12 isolated natural products, uvaretin (4) showed activity against the Gram-positive bacterium Bacillus subtilis with a MIC value of 18 µM. None of the isolated metabolites was active against the Gram-negative Escherichia coli at a ∼5 mM (2000 µg/mL) concentration. Whereas 4 showed cytotoxicity at EC50 10.2 µM against the MCF-7 human breast cancer cell line, the other compounds were inactive or not tested.

A New Benzopyranyl Cadenane Sesquiterpene and Other Antiplasmodial and Cytotoxic Metabolites from Cleistochlamys kirkii.

Phytochemical investigations of ethanol root bark and stem bark extracts of Cleistochlamys kirkii (Benth.) Oliv. (Annonaceae) yielded a new benzopyranyl cadinane-type sesquiterpene (cleistonol, 1) alongside 12 known compounds (2-13). The structures of the isolated compounds were established from NMR spectroscopic and mass spectrometric analyses. Structures of compounds 5 and 10 were further confirmed by single crystal X-ray crystallographic analyses, which also established their absolute stereochemical configuration. The ethanolic crude extract of C. kirkii root bark gave 72% inhibition against the chloroquine-sensitive 3D7-strain malaria parasite Plasmodium falciparum at 0.01 µg/mL. The isolated metabolites dichamanetin, (E)-acetylmelodorinol, and cleistenolide showed IC50 = 9.3, 7.6 and 15.2 µM, respectively, against P. falciparum 3D7. Both the crude extract and the isolated compounds exhibited cytotoxicity against the triple-negative, aggressive breast cancer cell line, MDA-MB-231, with IC50 = 42.0 µg/mL (crude extract) and 9.6-30.7 µM (isolated compounds). Our findings demonstrate the potential applicability of C. kirkii as a source of antimalarial and anticancer agents.