Ficus plants: State of the art from a phytochemical, pharmacological, and toxicological perspective.

Ficus genus is typically tropical plants and is among the earliest fruit trees cultivated by humans. Ficus carica L. is the common fig, Ficus benjamina L. is the weeping fig, and Ficus pumila L. is the creeping fig. These species are commonly used in traditional medicine for a wide range of diseases and contain rich secondary metabolites that have shown diverse applications. This comprehensive review describes for Ficus genus the phytochemical compounds, traditional uses and contemporary pharmacological activities such as antioxidant, cytotoxic, antimicrobial, anti-inflammatory, antidiabetic, antiulcer, and anticonvulsant. An extended survey of the current literature (Science Direct, Scopus, PubMed) has been carried out as part of the current work. The trends in the phytochemistry, pharmacological mechanisms and activities of Ficus genus are overviewed in this manuscript: antimicrobial, antidiabetic, anti-inflammatory and analgesic activity, antiseizure and anti-Parkinson's diseases, cytotoxic and antioxidant. Health-promoting effects, recent human clinical studies, safety and adverse effects of Ficus plants also are covered. The medical potential and long-term pharmacotherapeutic use of the genus Ficus along with no serious reported adverse events, suggests that it can be considered as being safe.

Identification of Human Kinin-Forming Enzyme Inhibitors from Medicinal Herbs.

The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein-kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.

Evaluation of Triazole and Isoxazole Derivatives as Potential Anti-infective Agents.

A series of isoxazole and triazole derivatives, with interesting bioactive scaffolds, were examined for their in vitro antibacterial, antifungal, and antiprotozoal activities. These compounds exhibited antitrypanosomal activity comparable to difluoromethylornithine (DMFO), a drug used in the treatment of human African trypanosomiasis. Isoxazole analogues 1, 3 and 4, and triazole derivatives 16, 17, 28, 37, 40 and 42 showed the highest antitrypanosomal activity with IC50 values of 17.89, 1.82, 10.38, 10.26, 11.77, 9.29, 3.93, 2.11, and 0.93 µM, respectively. Compounds 40 and 42 showed the most potent activity against Leishmania donovani amastigotes with IC50 values of 18.28 and 10.54 µM, respectively. Compound 42 showed the most potent activity against Leishmania donovani macrophage internalized amastigotes with an IC50 value of 8.32 µM. Conjugate triazoles 40-43 displayed potential antimalarial activity against chloroquine-resistant W2 and chloroquine sensitive D6 Plasmodium falciparum strains (IC50 value range from 0.58 to 8.36 µM). Compound 37 showed antibacterial activity against Staphylococcus aureus, MRSA and Mycobacterium intracellulare with IC50 values of 15.53, 14.22 and 47.45 µM, respectively. None of the compounds exhibited antifungal activity.

Flavonoids from Perovskia atriplicifolia and Their in Vitro Displacement of the Respective Radioligands for Human Opioid and Cannabinoid Receptors.

Bioassay-guided fractionation of the leaves of Perovskia atriplicifolia (Russian sage) resulted in the isolation of four previously known flavonoid derivatives, 5-hydroxy-6,7,3',4'-tetramethoxyflavone (1), 5,7-dihydroxy-6,3',4'-trimethoxyflavone (2), 5-hydroxy-6,7,4'-trimethoxyflavone (3), and 5,7-dihydroxy-6,4'-dimethoxyflavone (4). Compounds 1, 3, and 4 showed displacement of the radioligand for the cloned human δ opioid receptor with Ki values ranging from 3.1 to 26.0 µM. In addition, the binding mode of the compounds in the active site of the δ opioid receptor was investigated through molecular modeling algorithms. This study may have implications in better understanding non-nitrogenous δ opioid receptor ligands.

Synthesis and Cytotoxicity of Thieno[2,3-b]Pyridine Derivatives Toward Sensitive and Multidrug-Resistant Leukemia Cells.

A new series of substituted ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a-e were prepared by utilizing ethyl 2-chloro-7-cyclopropyl-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (1) and replacing of the 2-chlorine with anions obtained from phenol (2a), salicylaldehyde derivatives 2b-d or thiophenol (2e), leading to the respective ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a-e. The new compounds were evaluated for their in vitro cytotoxicity towards sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The screening revealed that compounds 3a, 3b, and 3e inhibited the growth of both cell lines. Compound 3b, with a phenol moiety, exhibited the highest growth inhibitory activity against CEM/ADR5000 and CCRF-CEM cells with IC50 values 4.486 ± 0.286 and 2.580 ± 0.550 µM, respectively. Collectively, the presented results demonstrate that the synthesized thieno[2,3-b]pyridines warrant further exploration for potential use as anti-cancer agents.

Sulfated phenolic compounds from Limonium caspium: Isolation, structural elucidation, and biological evaluation.

Three new compounds, (2S,3S)-5-methyldihydromyricetin (1), (2S,3S)-5-methyldihydromyricetin-3'-O-sulfate (2) and ß-d-glucopyranoside, 3-methyl, but-3-en-1-yl 4-O-α-l-rhamnopyranosyl (3) have been isolated from the Limonium caspium, together with dihydromyricetin (4), dihydromyricetin-3'-O-sulfate (5), myricetin-3'-O-sulfate (6), 5-methylmyricetin (7), myricetin (8), myricetin-3-O-ß-glucoside (9), as well as phloridzin (10), and tyramine (11). Compounds 5 and 6 were isolated for the first time as acids. This is the first report of all these compounds from this plant. Their structures were established by extensive NMR studies ((1)H NMR, (13)C NMR, DEPT, (1)H-(1)H COSY, HSQC, HMBC) as well as HRESIMS. All isolated compounds were evaluated for their antibacterial, antifungal, antimalarial and antileishmanial activities. Compounds 7, 8 and 9 exhibited good antifungal activity against Candida glabrata with IC50 values of 6.79, 15.37 and 8.53µg/mL, respectively. Compound 8 displayed significant antimalarial activity against resistant and sensitive strains of Plasmodium falciparum with IC50 values of 1.82 and 1.51µg/mL, respectively. Compounds 1, 4, 6, 8 and 9 showed excellent activity against Trypanosoma brucei with IC50 values of 6.93, 9.65, 8.52, 7.67 and 6.31µg/mL, respectively. To date, this is the first report on the phytochemical and biological activity of secondary metabolites from L. caspium.

Flavanones from Miconia prasina.

A glycosidic flavanone miconioside C (1) has been isolated from the methanolic extract of the stems of Miconia prasina, together with 7-O-ß-D-apiofuranosyl-(1→6)-ß-D-glucopyranosylmatteucinol (2), miconioside B (3), matteucinol (4), farrerol (5) and desmethoxymatteucinol (6). Their structures were mainly established by extensive NMR studies (1H NMR, 13C NMR, DEPT, 1H-1H COSY, HSQC, HMBC) and mass spectrometry. The compounds 1- 3 were evaluated for in vitro binding assays using cannabinoid receptors (CB1 and CB2).

Antifungal compounds from turmeric and nutmeg with activity against plant pathogens.

The antifungal activity of twenty-two common spices was evaluated against plant pathogens using direct-bioautography coupled Colletotrichum bioassays. Turmeric, nutmeg, ginger, clove, oregano, cinnamon, anise, fennel, basil, black cumin, and black pepper showed antifungal activity against the plant pathogens Colletotrichum acutatum, Colletotrichum fragariae, and Colletotrichum gloeosporioides. Among the active extracts, turmeric and nutmeg were the most active and were chosen for further investigation. The bioassay-guided fractionation led to the isolation of three compounds from turmeric (1-3) and three compounds from nutmeg (4-6). Their chemical structures were elucidated by spectroscopic analysis including HR-MS, 1D, and 2D NMR as curcumin (1), demethoxycurcumin (2) and bisdemethoxy-curcumin (3), erythro-(7R,8R)-Δ(8')-4,7-dihydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan (4), erythro-(7R,8R)-Δ8'-7-acetoxy-3,4,3',5'-tetra-methoxy-8-O-4'-neolignan (5), and 5-hydroxy-eugenol (6). The isolated compounds were subsequently evaluated using a 96-well microbioassay against plant pathogens. At 30 µM, compounds 2 and 3 possessed the most antifungal activity against Phomopsis obscurans and Phomopsis viticola, respectively.

Secondary metabolites from the fungus Emericella nidulans.

A new polyketide derivative koninginin H (1), has been isolated from the fungus Emericella nidulans, together with koninginin E (2), koninginin A (3), trichodermatide B (4), citrantifidiol (5), (4S,5R)-4-hydroxy-5-methylfuran-2-one (6), the glycerol derivatives gingerglycolipid B (7), (2S)-bis[9Z,12Z]-1-O, 2-O-dilinoleoyl-3-O-[alpha-D-galactopyranosyl-(1" --> 6') beta-D-galactopyranosyl]glycerol (8), (2S)-bis[9Z,12Z]-1-O, 2-O-dilinoleoyl-3-O-beta-D-galactopyranosylglycerol (9), the cerebroside flavuside B (10), and the known sterols beta-sitosterol glucoside and ergosta-5,7,22-trien-3-ol. Their structures were established by extensive NMR studies (1H NMR, 13C NMR, DEPT, 1H-1H COSY, HSQC, HMBC) and mass spectrometry. The antibacterial, antimalarial, antifungal and antileishmanial activities of compounds 1-10 were examined and the results indicated that compound 4 showed good antifungal activity against Cryptococcus neoformans with an IC50 value of 4.9 microg/mL.

Fatty acids with in vitro binding affinity for human opioid receptors from the fungus Emericella nidulans.

Bioassay-guided fractionation of the EtOAc extracts of the epiphytic fungus Emericella nidulans resulted in the isolation of a mixture of two fatty acids. This mixture showed 98% binding affinity to human δ opioid receptor. These two fatty acids were identified as palmitic (PAM), 1, and linoleic acids (LNA), 2, by 1D NMR as well as by GC/MS analysis, after their methylation. We found that different ratio mixtures of 1 and 2 showed variations in selective binding activities to human δ opioid receptors. Five more fatty acids, arachidonic acid (ARA), 3, cis-4,7,10,13,16,19-docosahexanoic acid (DHA), 4, cis-5,8,11,14,17-eicosapentaenoic acid (EPA), 5, linolenic acid (ALA), 6, and γ-linolenic acid (GLA), 7, were evaluated for their binding affinity for opioid receptors. ARA, 3, displayed affinity to δ and µ human opioid receptors with 68% and 80%, respectively. GLA, 7, showed selective binding affinity to µ receptor with a value of 55%. These findings provide fascinating insight into the use of foods with high concentrations of fatty acids.

Antifungal activity against plant pathogens of metabolites from the endophytic fungus Cladosporium cladosporioides.

Bioassay-guided fractionation of Cladosporium cladosporioides (Fresen.) de Vries extracts led to the isolation of four compounds, including cladosporin, 1; isocladosporin, 2; 5'-hydroxyasperentin, 3; and cladosporin-8-methyl ether, 4. An additional compound, 5',6-diacetylcladosporin, 5, was synthesized by acetylation of compound 3. Compounds 1-5 were evaluated for antifungal activity against plant pathogens. Phomopsis viticola was the most sensitive fungus to the tested compounds. At 30 µM, compound 1 exhibited 92.7, 90.1, 95.4, and 79.9% growth inhibition against Colletotrichum acutatum , Colletotrichum fragariae , Colletotrichum gloeosporioides , and P. viticola, respectively. Compound 2 showed 50.4, 60.2, and 83.0% growth inhibition at 30 µM against Co. fragariae, Co. gloeosporioides, and P. viticola, respectively. Compounds 3 and 4 were isolated for the first time from Cl. cladosporioides. Moreover, the identification of essential structural features of the cladosporin nuclei has also been evaluated. These structures provide new templates for the potential treatment and management of plant diseases.