In Vitro and Molecular Docking Evaluation of the Anticholinesterase and Antidiabetic Effects of Compounds from Terminalia macroptera Guill. & Perr. (Combretaceae).

Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are suitable therapies for AD, while α-amylase and α-glucosidase inhibitors are employed as antidiabetic agents. Compounds were isolated from the medicinal plant Terminalia macroptera and evaluated for their AChE, BChE, α-amylase, and α-glucosidase inhibitions. From 1H and 13C NMR data, the compounds were identified as 3,3'-di-O-methyl ellagic acid (1), 3,3',4'-tri-O-methyl ellagic acid-4-O-ß-D-xylopyranoside (2), 3,3',4'-tri-O-methyl ellagic acid-4-O-ß-D-glucopyranoside (3), 3,3'-di-O-methyl ellagic acid-4-O-ß-D-glucopyranoside (4), myricetin-3-O-rhamnoside (5), shikimic acid (6), arjungenin (7), terminolic acid (8), 24-deoxysericoside (9), arjunglucoside I (10), and chebuloside II (11). The derivatives of ellagic acid (1-4) showed moderate to good inhibition of cholinesterases, with the most potent being 3,3'-di-O-methyl ellagic acid, with IC50 values of 46.77 ± 0.90 µg/mL and 50.48 ± 1.10 µg/mL against AChE and BChE, respectively. The compounds exhibited potential inhibition of α-amylase and α-glucosidase, especially the phenolic compounds (1-5). Myricetin-3-O-rhamnoside had the highest α-amylase inhibition with an IC50 value of 65.17 ± 0.43 µg/mL compared to acarbose with an IC50 value of 32.25 ± 0.36 µg/mL. Two compounds, 3,3'-di-O-methyl ellagic acid (IC50 = 74.18 ± 0.29 µg/mL) and myricetin-3-O-rhamnoside (IC50 = 69.02 ± 0.65 µg/mL), were more active than the standard acarbose (IC50 = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay. For α-glucosidase and α-amylase, the molecular docking results for 1-11 reveal that these compounds may fit well into the binding sites of the target enzymes, establishing stable complexes with negative binding energies in the range of -4.03 to -10.20 kcalmol-1. Though not all the compounds showed binding affinities with cholinesterases, some had negative binding energies, indicating that the inhibition was thermodynamically favorable.

Polyoxygenated Stigmastane-Type Steroids from Vernonia kotschyana Sch. Bip. ex Walp. and Their Chemophenetic Significance.

Four polyoxygenated stigmastanes (1-4) alongside known analogues (7-8) and flavonoids (5-6) were isolated from a dichloromethane/methanol (1:1, v/v) extract of the whole plant of Vernonia kotschyana Sch. Bip. ex Walp. (Asteraceae). Their structures were determined by means of spectroscopic and spectrometric analysis. The relative stereochemistry of the new compounds was established and confirmed via biosynthesis evidence and cyclization of 1 under acidic conditions. A plausible biosynthetic pathway to the new compounds and the chemophenetic significance of the isolated constituents were also discussed. The crude extract, fractions, and compounds (1-3) were assessed for their antibacterial activity against five highly prevalent bacterial strains. The fractions and compounds showed low to moderate activity with minimal inhibitory concentrations (MICs) > 125 µg/mL.

Bioactive Secondary Metabolites from Fungi of the Genus Cytospora Ehrenb. (Ascomycota).

Cytospora is a genus of fungi belonging to the Cytosporaceae family (Sordariomycetes, Ascomycota) considered as a prolific source of specialized metabolites due to their ability to produce diverse secondary metabolites with a broad range of biological activities. Since the first chemical investigation of this genus in the 1980s, further studies have led to the isolation and structural elucidation of several bioactive compounds including cytosporones, nonanolides, macrocyclic dilactones, and terpenoids. This review summarizes, for the first time, the chemical diversity of bioactive secondary metabolites from the genus Cytospora and highlights its potential as an alternative source of secondary metabolites for pharmacological studies. Moreover, this review will serve as a basis for future investigations of compounds of this genus.

Antibacterial Flavonoids and Other Compounds from the Aerial Parts of Vernonia guineensis Benth. (Asteraceae).

An extensive phytochemical study of the aerial parts of Vernonia guineensis Benth. (Asteraceae) led to the isolation of a new flavone, vernoguinoflavone and a naturally isolated glycerol ester, eicosanoic acid 2-hydroxy-1,3-propanediyl ester, together with eighteen known secondary metabolites including quercetin, luteolin, vernopicrin, vernomelitensin, ß-amyrin, oleanolic acid, ursolic acid, lupeol, betulinic acid, ß-carotene, a mixture of stigmasterol and ß-sitosterol, ß-sitosterol-3-O-ß-D-glucoside, 2,3-dihydroxypropyl heptacosanoate, pentacosanoic acid, docosan-1-ol, tritriacontan-1-ol, and heptatriacontan-1-ol. Eleven compounds are reported herein for the first time from this species. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses, particularly 1D and 2D NMR, and HR-ESI-MS and by comparison of their data with those reported in the literature. The crude extract, fractions and some isolated compounds were evaluated for their antibacterial activity against Gram-negative bacteria: Escherichia coli (ATCC 25922), Shigella flexineri (NR 518), Salmonella muenchen, Salmonella typhimurium and Salmonella typhi (ATCC 19430). All the tested compounds demonstrated inhibitory activities against the tested enteric bacteria with MIC values ranging from 3.12 to 100 µg/ml. Three flavonoids isolated from the most active fraction demonstrated the best bioactivities against Escherichia coli, Salmonella muenchen and Salmonella typhimurium with MIC values ranging from 3.12 to 25 µg/mL.

Diversity of African fungi, chemical constituents and biological activities.

Besides plants and animals, the fungal kingdom consists of several species characterized by various forms and applications. Fungi are amazing producers of bioactive natural products with applications in medicine and agriculture. Though this kingdom has been extensively investigated worldwide, it remains relatively underexplored in Africa. To address the knowledge gaps, encourage research interest, and suggest opportunities for the discovery of more bioactive substances from African fungi, we considered it appropriate to extensively review the research work carried out on African fungi since 1988. This review summarizes the diversity and distribution of fungi throughout Africa, the secondary metabolites yet reported from studied fungi, their biological activities and, the countries where they were collected. The studied fungi originated from eleven African countries and were mainly endophytic fungi and higher fungi (macrofungi). Their investigation led to the isolation of five hundred and three (503) compounds with polyketides representing the main class of secondary metabolites. The compounds exhibited varied biological activities with antibacterial and antiproliferative properties being the most prominent.

The genus Canthium: A comprehensive summary on its traditional use, phytochemistry, and pharmacological activities.

Canthium Lam. is a genus of flowering plants of the Rubiaceae family with about 80-102 species mainly distributed in Asia, tropical and subtropical Africa. The genus is closely related to Keetia E. Phillips and Psydrax Gaertn. and plants of this genus are used in folk medicine for the treatment of diarrhea, worms, leucorrhoea, constipation, snake bites, diabetes, hypertension, venereal diseases, and malaria. The present review covers a period of 52 years of biological and chemical investigations into the genus Canthium and has resulted in the isolation of about 96 secondary metabolites and several reported biological properties. For the Rubiaceae family, iridoids were reported as being the chemotaxonomic markers of this genus (∼25%). Other reported classes of compounds include alkaloids, flavonoids, phenolic compounds, cyanogenic glycosides, coumarins, sugar alcohols, lignans, triterpenoids, and benzoquinones. The main reported pharmacological properties of most species of this genus include antioxidant, antiplasmodial, antipyretic, anti-inflammatory, antidiabetic, neuroprotective and antimicrobial activities with the latter being the most prominent. Considering the diversity of compounds reported from plants of this genus and their wide range of biological activities, it is considered to be worthy to further investigate them for the discovery of potentially new and cost effective drugs.

Chitosan-Based Nanoencapsulated Essential Oils: Potential Leads against Breast Cancer Cells in Preclinical Studies.

Since ancient times, essential oils (EOs) derived from aromatic plants have played a significant role in promoting human health. EOs are widely used in biomedical applications due to their medicinal properties. EOs and their constituents have been extensively studied for treating various health-related disorders, including cancer. Nonetheless, their biomedical applications are limited due to several drawbacks. Recent advances in nanotechnology offer the potential for utilising EO-loaded nanoparticles in the treatment of various diseases. In this aspect, chitosan (CS) appears as an exceptional encapsulating agent owing to its beneficial attributes. This review highlights the use of bioactive EOs and their constituents against breast cancer cells. Challenges associated with the use of EOs in biomedical applications are addressed. Essential information on the benefits of CS as an encapsulant, the advantages of nanoencapsulated EOs, and the cytotoxic actions of CS-based nanoencapsulated EOs against breast cancer cells is emphasised. Overall, the nanodelivery of bioactive EOs employing polymeric CS represents a promising avenue against breast cancer cells in preclinical studies.

Atricephenols A and B, two phenolic compounds from Indigofera atriceps Hook.f. (Fabaceae).

The phytochemical investigation of a previously unstudied species of the genus Indigofera, I. atriceps Hook.f. was undertaken and two new phenolic compounds, atricephenols A (1) and B (2) were isolated, along with nine known secondary metabolites viz., (-)-melilotocarpan D (3), genistein (4), melilotocarpan A (5), maackiain (6), p-hydroxybenzaldehyde (7), bornesitol (8), ß-sitosterol (9), sitosterol-3-O-ß-D-glucopyranoside (10) and stigmasterol-3-O-ß-D-glucopyranoside (11). Their structures were elucidated by extensive NMR spectroscopic analyses and HRESIMS, and by comparing their data with those reported in the literature. Compounds 1, 4, 7-11 were tested for their antibacterial efficacies and for their potential to inhibit the enzyme urease. Compounds 7 and 9 showed significant antibacterial activity against Salmonella typhi (ZOIs of 13 and 15 mm, respectively), while the best urease inhibition was measured for compound 9 with an IC50 value of 18.6 µM, which is higher than that of the potent inhibitor, thiourea (IC50 = 21.5 µM).

Potentiation effect of mallotojaponin B on chloramphenicol and mode of action of combinations against Methicillin-resistant Staphylococcus aureus.

Staphylococcus aureus, the causative agent of many infectious diseases has developed resistance to many antibiotics, even chloramphenicol which was the essential antibiotic recommended for the treatment of bacterial infection. Thus, other alternatives to fight against S. aureus infections are necessary; and combinatory therapy of antibiotics with natural compounds is one of the approaches. This study evaluated the activity of the combination of mallotojaponin B and chloramphenicol against Methicillin-resistant Staphylococcus aureus (MRSA). Antibacterial activities were evaluated by broth microdilution and the checkerboard methods. Modes of action as time-kill kinetic, Nucleotide leakage, inhibition and eradication of biofilm, and loss of salt tolerance were evaluated. Cytotoxicity was evaluated on Vero and Raw cell lines. Mallotojaponin B showed good activity against MRSA with a MIC value of 12.5 µg/mL. MRSA showed high resistance to chloramphenicol (MIC = 250 µg/mL). The combination produced a synergistic effect with a mean FICI of 0.393. This combination was bactericidal, inducing nucleotide leakage, inhibiting biofilm formation, and eradicating biofilm formed by MRSA. The synergic combination was non-cytotoxic to Vero and Raw cell lines. Thus, the combination of mallotojaponin B and chloramphenicol could be a potential alternative to design a new drug against MRSA infections.

Identification of 3,3'-O-dimethylellagic acid and apigenin as the main antiplasmodial constituents of Endodesmia calophylloides Benth and Hymenostegia afzelii (Oliver.) Harms.

BACKGROUND: Endodesmia calophylloides and Hymenostegia afzelii belong to the Guttiferae and Caesalpiniaceae plant families with known uses in African ethno-medicine to treat malaria and several other diseases. This study aimed at identifying antiplasmodial natural products from selected crude extracts from H. afzelii and E. calophylloides and to assess their cytotoxicity. METHODS: The extracts from H. afzelii and E. calophylloides were subjected to bioassay-guided fractionation to identify antiplasmodial compounds. The hydroethanol and methanol stem bark crude extracts, fractions and isolated compounds were assessed for antiplasmodial activity against the chloroquine-sensitive 3D7 and multi-drug resistant Dd2 strains of Plasmodium falciparum using the SYBR green I fluorescence-based microdilution assay. Cytotoxicity of active extracts, fractions and compounds was determined on African green monkey normal kidney Vero and murine macrophage Raw 264.7 cell lines using the Resazurin-based viability assay. RESULTS: The hydroethanolic extract of H. afzelii stem bark (HasbHE) and the methanolic extract of E. calophylloides stem bark (EcsbM) exhibited the highest potency against both Pf3D7 (EC50 values of 3.32 ± 0.15 µg/mL and 7.40 ± 0.19 µg/mL, respectively) and PfDd2 (EC50 of 3.08 ± 0.21 µg/mL and 7.48 ± 0.07 µg/mL, respectively) strains. Both extracts showed high selectivity toward Plasmodium parasites (SI > 13). The biological activity-guided fractionation led to the identification of five compounds (Compounds 1-5) from HasbHE and one compound (Compound 6) from EcsbM. Of these, Compound 1 corresponding to apigenin (EC50 Pf3D7, of 19.01 ± 0.72 µM and EC50 PfDd2 of 16.39 ± 0.52 µM), and Compound 6 corresponding to 3,3'-O-dimethylellagic acid (EC50 Pf3D7 of 4.27 ± 0.05 µM and EC50 PfDd2 of 1.36 ± 0.47 µM) displayed the highest antiplasmodial activities. Interestingly, both compounds exhibited negligible cytotoxicity against both Vero and Raw 264.7 cell lines with selectivity indices greater than 9. CONCLUSIONS: This study led to the identification of two potent antiplasmodial natural compounds, 3,3'-O-dimethylellagic acid and apigenin that could serve as starting points for further antimalarial drug discovery.

Sensitive Determination of C-Alkylated Flavonoids by HPLC-ESI-MS/MS Using Multiple Reaction Monitoring Approach: Pseudarthria hookeri as a Case Study.

One of the major problems with the formulation of herbal medicines is the quality control of plant material to ensure its efficacy and safety. Quality control of medicinal plants requires analysis of many bioactive compounds present in the plant. C-alkylated flavonoids are an important bioactive subclass of flavonoids. A simple, rapid, sensitive and selective method is presented here for the quantification of bioactive C-alkylated flavonoids. This is the first quantitative method for analysis of C-alkylated flavonoids based on the multiple reaction monitoring (MRM) approach so far. This study focuses on method development for quantification of bioactive C-alkylated flavonoids. Quantification of a total of five C-alkylated flavonoids was done employing the MRM approach on an HPLC-QqQ-MS instrument. LODs and LOQs for quantified flavonoids were in the range of 0.41-1.32 and 1.23-3.96 ng/mL, respectively. Linear calibration curves between 25 and 1500 ng/mL were obtained with the regression coefficients of ≥0.996. Accuracy (% bias) and precision (% RSD) of the analyses were found to be less than 5%. Developed HPLC-ESI-MS/MS can be employed as a quality control method of plant raw materials.

Antibacterial phloroglucinols derivatives from the leaves of Mallotus oppositifolius (Geisler) Müll. Arg. (Euphorbiaceae).

From the ethno-medicinally used leaves of Mallotus oppositifolius, four acylphloroglucinol derivatives, namely Acronyculatin SU (1-3) and Mallotojaponin D (4) were isolated along with seven known compounds (5-11). Structures were elucidated by comprehensive spectroscopic analyses and HRMS data. Absolute configurations were assigned by careful comparison of their specific optical rotation with those of closely related compounds. Compounds 1, 2, 6 and 11 demonstrated inhibitory activity against the bacterial strains E. coli, S. aureus, S. typhi, P. aeruginosa with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50 µg/ml.