The Roots of Neorautanenia mitis (A. Rich) Verdcourt: Further Evidence of Its Antidiarrhoeal Activity.

Despite the current management options and therapeutics used in the treatment of diarrhoea, in Africa and Asia, diarrhoea remains a major concern, especially in children under the age of 5 years. Traditional knowledge of medicinal plants used in the management of diarrhoea symptoms can be explored for their efficacy. In Nigeria, the TMPs (Traditional Medicine Practitioners) have, over the years, employed medicinal plants in the management of diarrhoea symptoms. In our current and previous studies, we aimed at validating the effectiveness of Neorautanenia mitis in the management of diarrhoea as claimed by the TMPs. Out of the 20 compounds isolated from N. mitis, the compounds neodulin, pachyrrhizine, neotenone and dolineone were the most abundant, and in this study, neodulin showed a pronounced relaxation of the rhythmic contraction of the isolated rabbit jejunum in an organ bath in a concentration-dependent manner, with a complete relaxation at 60 µg/mL. Neotenone and dolineone showed a dose-dependent inhibition of defecation of 65.07%, and 50.01%, respectively, at 20 mg/kg in a castor-oil-induced diarrhoea model. This is a strong indication that compounds from N. mitis possess antidiarrhoeal properties, thereby giving credence to its traditional usage in diarrhoea therapy, and therefore validating its antidiarrhoeal activity and its being worthy of further investigation.

Isolation of bioactive compounds from medicinal plants used in traditional medicine: Rautandiol B, a potential lead compound against Plasmodium falciparum.

BACKGROUND: Neorautanenia mitis, Hydnora abyssinica, and Senna surattensis are medicinal plants with a variety of traditional uses. In this study, we sought to isolate the bioactive compounds responsible for some of these activities, and to uncover their other potential medicinal properties. METHODS: The DCM and ethanol extracts of the roots of N. mitis and H. abyssinica, and the leaves of S. surattensis were prepared and their phytochemical components were isolated and purified using chromatographic methods. These extracts and their pure phytochemical components were evaluated in in-vitro models for their inhibitory activities against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Mycobacterium tuberculosis, α-amylase (AA), and α-glucosidase (AG). RESULTS: Rautandiol B had significant inhibitory activities against two strains of Plasmodium falciparum showing a high safety ratio (SR) and IC50 values of 0.40 ± 0.07 µM (SR - 108) and 0.74 ± 0.29 µM (SR - 133) against TM4/8.2 and K1CB1, respectively. While (-)-2-isopentenyl-3-hydroxy-8-9-methylenedioxypterocarpan showed the highest inhibitory activity against T. brucei rhodesiense with an IC50 value of 4.87 ± 0.49 µM (SR > 5.83). All crude extracts showed inhibitory activities against AA and AG, with three of the most active phytochemical components; rautandiol A, catechin, and dolineon, having only modest activities against AG with IC50 values of 0.28 mM, 0.36 mM and 0.66 mM, respectively. CONCLUSION: These studies have led to the identification of lead compounds with potential for future drug development, including Rautandiol B, as a potential lead compound against Plasmodium falciparum. The relatively higher inhibitory activities of the crude extracts against AG and AA over their isolated components could be due to the synergistic effects between their phytochemical components. These crude extracts could potentially serve as alternative inhibitors of AG and AA and as therapeutics for diabetes.

Macluracochinones A-E, antimicrobial flavonoids from Maclura cochinchinensis (Lour.) Corner.

The phytochemical investigation of the fruit and leaf extracts of Maclura cochinchinensis (Lour.) Corner (Moraceae) resulted in the isolation and identification of four undescribed isoflavones (macluracochinones A-D) and one undescribed flavone (macluracochinone E), together with 24 known compounds. The structures of the undescribed compounds were elucidated using nuclear magnetic resonance (NMR) and high-resolution electrospray ionization time-of-flight mass spectrometry (HRESITOFMS) experiments. Gancaonin M, lupiwighteone, lupalbigenin, warangalone, auriculatin, and millexatin F displayed good antibacterial activities against Gram-positive bacteria with MIC values in the range of 1-8 µg/mL. Lupalbigenin showed strong activities against methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus with the same MIC value of 1 µg/mL.

Unique polyacetylenic ester-neolignan derivatives from Mitrephora tomentosa and their antimalarial activities.

The phytochemical investigation of the methanol extracts of the leaves and twigs of Mitrephora tomentosa Hook. f. & Thomson resulted in the isolation and identification of undescribed polyacetylenic ester-neolignan derivatives, along with six known compounds. These six undescribed natural products were named as mitrephentosins A-F. The structures of these compounds were determined by spectroscopic techniques including UV, IR, NMR, and mass spectrometric analyses. The absolute configurations of mitrephentosins A-F were determined based on specific rotations values and ECD spectral data by comparisons made with the known parent neoligan compound mitredrusin. Mitrephentosins C, E, and F showed moderate antimalarial activities (IC50 values of 13.3-24.6 µM) against the Plasmodium falciparum strains TM4/8.2 and K1CB1 and were not toxic to Vero cells, while the other isolated compounds were not active against these P. falciparum strains.

A new xanthone and a biphenyl from the flower and twig extracts of Garcinia mckeaniana.

The phytochemical investigation of the flower and twig extracts of Garcinia mckeaniana yielded a new xanthone, mckeanianone F (1) and a new biphenyl, mckeaniabiphenyl (2) together with 15 known compounds. The isolated compounds were characterized using spectroscopic techniques and mass spectrometry. Some of the isolated compounds from the twigs exhibited antimalarial and cytotoxic activities.

Cytotoxic and larvicidal activities of Stemona alkaloids from the aerial parts and roots of Stemona curtisii Hook.f.

A new Stemona alkaloid glycoside derivative, 6-hydroxy-5,6-seco-stemocurtisinoside (4), was isolated from the ethanolic extract of the aerial parts of Stemona curtisii Hook.f., together with stemocurtisine (1), (11Z)-1',2'-didehydrostemofoline (2) and 6-hydroxy-5,6-seco-stemocurtisine (3). Whereas, stemocurtisine (1), stemocurtisinol (5) and oxyprotostemonine (6) were isolated from the roots. Their structures were elucidated using 1D and 2D NMR spectroscopy as well as MS experiments. The extract and the pure isolated compounds were evaluated for their cytotoxicities and their larvicidal activities against the dengue vector, Aedes aegypti. The alkaloid 2 showed the strongest larvicidal activity with a LC50 value of 2.44 µM. While the alkaloid 3 exhibited cytotoxicity against MCF-7 and KB cells (IC50 values of 62.52 and 18.82 µM, respectively) and showed no significant cytotoxicity against Vero cells. Additionally, quantitative analysis of the most active compounds; 2 and 3 in the crude extracts was also performed by HPLC.

(R)-3-(8'-Hydroxyfarnesyl)-indole and other chemical constituents from the flowers of Anomianthus dulcis and their antimalarial and cytotoxic activities.

A new farnesylindole, (R)-3-(8'-hydroxyfarnesyl)-indole (1), as a scalemic mixture (33% ee) along with nine known compounds (2-10), including one farnesylindole, three flavanones, three flavone derivatives and two chalcone derivatives were isolated from the methanolic crude extract of the flowers from Anomianthus dulcis. All compounds were purified by appropriate chromatographic techniques and their structures elucidated by spectroscopic methods. Compounds 1, 2 and 8 showed moderate antiplasmodial activities against TM4/8.Two and K1CB1 strains of which compound 2 displayed the best activity with IC50 values of 27.9 ± 2.57 and 21.4 ± 1.68 µM, respectively. In addition, compound 1 also presented modest cytotoxicity against a KB cell line with an IC50 value of 22.3 ± 0.39 µM. None of these compounds showed cytotoxicity against Vero cells.

Isolation of CFTR and TMEM16A inhibitors from Neorautanenia mitis (A. Rich) Verdcourt: Potential lead compounds for treatment of secretory diarrhea.

A phytochemical study on the root extracts of Neorautanenia mitis, a Nigerian medicinal plant used in the management of diarrhea, led to the isolation of one new and 19 known natural products. These compounds and crude extracts were evaluated for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl- channel and calcium-activated Cl- channel (TMEM16A) inhibitory activities in T84 and Calu-3 cells, respectively. Four compounds namely dolineon, neodulin, pachyrrhizine, and neotenone inhibited cAMP-induced Cl- secretion across T84 cell monolayers with IC50 values of ~0.81 µM, ~2.42 µM, ~2.87 µM, and ~4.66 µM, respectively. Dolineon having the highest inhibitory activity also inhibited a Ca + activated Cl- channel (TMEM16A) with an IC50 value of ~4.38 µM. The in vitro antidiarrheal activity of dolineon was evaluated on cholera toxin (CT) induced chloride secretion in T84 cells, where it inhibited CT-induced chloride secretion by >70% at 100 µM. Dolineon also inhibited CT-induced fluid secretion by ~70% in an in vivo mouse closed loop model at a dose of 16.9 µg/loop. The cytotoxicity of the extracts and compounds was evaluated on KB, Vero and BHK21 cells, dolineon showed low cytotoxicity of >29.6 µM and 57.30 + 6.77 µM against Vero and BHK21 cells, respectively. Our study revealed that several compounds isolated from N. mitis showed antidiarrheal activity. The most active compound dolineon can potentially serve as a lead compound towards the development of CFTR and TMEM16A inhibitors as future therapeutics for secretory diarrhea.

α-Glucosidase inhibitory and nitric oxide production inhibitory activities of alkaloids isolated from a twig extract of Polyalthia cinnamomea.

The first phytochemical investigation of Polyalthia cinnamomea led to the isolation and identification of two new oxoprotoberberine alkaloids, (-)-(13aS)-polyalthiacinnamines A and B, together with eleven known compounds. The structures of the new compounds were elucidated by extensive spectroscopic methods. The absolute configuration of miliusacunine E and consanguine B was established by X-ray diffraction analysis using Cu Kα radiation and ECD spectra, whereas the absolute configurations of polyalthiacinnamines A and B were established by comparison of their ECD spectra and specific rotations with those of miliusacunine E and consanguine B. Compounds 1-4, 6, and 8 exhibited α-glucosidase inhibitory activities (IC50 values ranging from 11.3 to 57.9 µM) better than a positive control (acarbose, IC50 83.5 µM). Compound 2 also exhibited NO production inhibitory activity with an IC50 value of 24.4 µM (indomethacin, a positive control, IC50 = 32.2 µM).

Styryllactones from Goniothalamus tamirensis.

The phytochemical investigation of the twig and leaf extracts of Goniothalamus tamirensis led to the isolation and identification of 15 compounds including three rare previously undescribed styryllactones, goniotamirenones A-C, together with 12 known compounds. (Z)-6-Styryl-5,6-dihydro-2-pyranone and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one are reported here for the first time as previously undescribed natural products. Their structures were elucidated by spectroscopic methods. Goniotamirenone A was synthesized via a [2 + 2] cycloaddition reaction of 6-styrrylpyran-2-one in quantitative yield. The absolute configurations of goniotamirenones B and C were identified from experimental and calculated ECD data, while the absolute configurations of (-)-5-acetoxygoniothalamin, (-)-isoaltholactone, parvistone E, and 5-(1-hydroxy-3-phenyl-allyl)-dihydro-furan-2-one were identified by single-crystal X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of the other related compounds were determined from comparisons of their ECD spectra with relevant compounds reported in the literature. (-)-5-Acetoxygoniothalamin exhibited potent cytotoxicity against the colon cancer cell line (HCT116) with an IC50 value of 8.6 µM which was better than the standard control (doxorubicin, IC50 = 9.7 µM), while (Z)-6-styryl-5,6-dihydro-2-pyranone was less active with an IC50 value of 22.1 µM.

Antibacterial and cytotoxic activities of phenolic constituents from the stem extracts of Spatholobus parviflorus.

A new 2-arylbenzofuran, spathobenzofuran (1), together with ten known compounds including a 2-arylbenzofuran, three pterocarpans and six isoflavones were isolated from the acetone crude extract of the stems of Spatholobus parviflorus. All compounds were characterised by spectroscopic methods. Compound 4 was active (MIC 8 µg/mL) against Gram-negative Pseudomonas aeruginosa TISTR 781 while compound 2 had modest activity against Gram-positive Staphylococcus aureus TISTR 1466 with a MIC value of 16 µg/mL. All isolated compounds showed no cytotoxicity against Vero and KB cells.

Potent α-glucosidase inhibitory activity of compounds isolated from the leaf extracts of Uvaria hamiltonii.

The phytochemical investigation of the leaf extracts of Uvaria hamiltonii (Annonaceae) led to the isolation and identification of ten compounds including a new seco-cyclohexene (1) together with nine known compounds (2-10). Their structures were elucidated by intensive analysis by spectroscopic methods and comparisons of their spectroscopic data with those of compounds reported in the literature. Compounds 2, 8, and 9 showed potent α-glucosidase inhibitory activity with the IC50 values ranging from 2.6-7.1 µM.

Dasymaschalolactams A-E, Aristolactams from a Twig Extract of Dasymaschalon dasymaschalum.

Five new aristolactam alkaloids (1-5), dasymaschalolactams A-E, and the first isolation of dasymaschalolactone (17) as a natural product, together with 19 known compounds (6-16 and 18-25) were isolated from the twig extract of Dasymaschalon dasymaschalum. Their structures were elucidated by spectroscopic methods as well as comparisons made from the literature. Compounds 20 and 21 showed α-glucosidase inhibitory activities with IC50 values of 4.5 and 24.7 µM, respectively.

Uvarialuridols A-C, three new polyoxygenated cyclohexenes from the twig and leaf extracts of Uvaria lurida.

The first phytochemical investigation of Uvaria lurida resulted in the isolation and identification of three new polyoxygenated cyclohexenes, (+)-(1R,2S,3R,6S)-uvarialuridols A-C (1-3), together with 10 known compounds (4-13). All new structures were elucidated by spectroscopic methods and HRESIMS. The absolute configurations of compounds 1 and 5 were confirmed by X-ray diffraction analysis using Cu Kα radiation. The absolute configurations of compounds 2-4 were identified from comparisons of their specific rotations and ECD spectra with those of known compounds. Compound 11 showed α-glucosidase inhibitory activity with an IC50 value of 30 µM which was better than the standard control, acarbose (74 µM) whereas, compound 10 exhibited nitric oxide (NO) production inhibitory activity with an IC50 value of 37 µM.

Utilization of electrocoagulation for the isolation of alkaloids from the aerial parts of Stemona aphylla and their mosquitocidal activities against Aedes aegypti.

The electrocoagulation (EC) technique is an alternative method of isolating natural products with the advantage of minimizing the amounts of organic solvents required for this process, which are often harmful to the environment. In this research, the EC and the conventional solvent extraction methods were used in the isolation of Stemona alkaloids from the aerial parts of Stemona aphylla. A comparison was made between the amounts of the isolated alkaloids and the solvents used. The isolated alkaloids were evaluated for their larvicidal, ovicidal and oviposition-deterrent activities against the dengue vector, Aedes aegypti. The morphology and histopatology of the alkaloid treated larvae were also investigated. Two Stemona alkaloids, (2'S)-hydroxystemofoline and stemofoline, were isolated from both the EC and the conventional method. The amounts of (2'S)-hydroxystemofoline from the EC method was about the same as that obtained from the conventional method. However, the amounts of stemofoline obtained from the EC method were about two times larger than those obtained from the conventional method. Importantly, the EC method required six times less total organic solvents. The larvicidal activity assays of (2'S)-hydroxystemofoline and stemofoline showed that these were highly effective against Aedes aegypti larvae with LC50 values of 3.91 µg/ml and 4.35 µg/ml, respectively. Whereas, the crude EC extract (LC50 = 11.86 µg/ml) showed greater larvicidal activity than the crude extract obtained from the conventional extraction method (LC50 = 53.40 µg/ml). The morphological observations of the (2'S)-hydroxystemofoline and the stemofoline treated larvae revealed that the anal gills were the sites of aberrations. A histopathological study showed that larvae treated with these alkaloids had cytopathological alterations to the epithelial cells of the midgut. At a concentration 40 µg/ml (2'S)-hydroxystemofoline showed 100% ovicidal activity on 24 h old eggs while stemofoline showed 97.2%. Furthermore, the oviposition-deterrent effects of (2'S)-hydroxystemofoline and stemofoline, at a concentration of 80 µg/ml were 99.5% and 97.2%, respectively.

A tocotrienol quinone dimer and xanthones from the leaf extract of Garcinia nigrolineata.

Four new compounds (1-4) together with six known compounds (5-10) were isolated from the leaf extract of Garcinia nigrolineata. Compound 4 is a rare tocotrienol quinone dimer. The structures were elucidated based on NMR and MS data. All isolated compounds were evaluated for their antibacterial activities.

α-Glucosidase Inhibitory Flavonoids and Oxepinones from the Leaf and Twig Extracts of Desmos cochinchinensis.

Four new flavonoids (1-4), a new benzyl benzoate derivative (5), five new oxepinones (6-10), and 14 known compounds (11-24) were isolated from the leaf and twig extracts of Desmos cochinchinensis. Their structures were established by spectroscopic methods. The structure of 1 was also confirmed by X-ray diffraction data. The absolute configurations of 3, 4, and 6-10 were determined from comparisons of their ECD spectra with those of relevant reported compounds. Compounds 1, 2, 6, 8, 10, 12-15, and 17 showed α-glucosidase inhibitory activities with IC50 values ranging from 0.2 to 4.9 µM.

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model.

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 µg/mL against methicillin-resistant Staphylococcus aureus and 8 µg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 µg/mL), Pseudomonas aeruginosa (8 µg/mL) and Klebsiella pneumoniae (16 µg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.

Amides and Flavonoids from the Fruit and Leaf Extracts of Melodorum siamensis.

Four new chalcones (1, 10, 13, and 14), a new flavanone, (9), a new amide (8), and 19 known compounds were acquired from Melodorum siamensis. The structures were established by NMR and MS data analyses. Compounds 1 (er 1.4:1) and 2 (er 1.1:1) were scalemic and were resolved to yield (-)-1 and (+)-1 and (-)-2 and (+)-2, respectively. The absolute configurations of these compounds were determined from experimental and calculated ECD data. The structures and configurations of (-)-2 and (+)-8 were identified by single-crystal X-ray diffraction analysis. Compound 11 showed nuclear factor-κB inhibitory effects (IC50 = 9 µM) in a pancreatic ß cell line (MIN-6 cells).

Polyoxygenated Cyclohexenes and Their Chlorinated Derivatives from the Leaves of Uvaria cherrevensis.

The chemical study of leaf extracts from Uvaria cherrevensis resulted in the identification of 11 new polyoxygenated cyclohexenes, cherrevenols A-K (1-11), and a new seco-cyclohexene derivative, cherrevenol L (12). Nine known compounds (13-21) were also isolated. Three of the isolated compounds are chlorinated polyoxygenated cyclohexenes. The structures of these compounds were determined using spectroscopic methods and, in some cases (compounds 2, 6, 8, and 10), single-crystal X-ray crystallographic structural analysis or chemical correlation (compounds 6 and 7). Compounds 6 and 7 were both isolated as scalemic mixtures (ee 23-24%).