Current Bioactive Compounds - Volume 16, Issue 7, 2020

Background: Antioxidants are the substances that interact inside and outside of a biological system against the damaging effects of highly reactive free radicals produced during metabolism. Among various natural alternative sources of bioactive metabolites, endophytic fungi have emerged as a significant reservoir of potent antioxidant compounds. These scantly explored micro-organisms are prolific producers of novel compounds and have the capability to produce metabolites that are exclusively isolated from Plantae. A wide array of compounds like nucleobases, polyketides, terpenoids, flavonoids, coumarins, xanthones, semiquinones, peptides, and phenolic acids have been identified as natural antioxidants produced by these micro-organisms. Methods: A detailed review of the literature published recently was undertaken using bibliographic database like Sci-finder and Google scholar. Questions to be reviewed and criteria for selection as a part of the study were fixed. The key features like information on the structure of isolated metabolites and antioxidant activities were summarised after a critical examination. A skeleton was established which gives insight into the type of novel chemical moieties which can be explored as a future antioxidant (s). Results: The review substantially covers the recently discovered compounds, in the period 2013 – 2018, having potent antioxidant activity, isolated from endophytic fungi colonizing diverse plant types such as terrestrial plants, mangrove plants and marine algae. Among the 96 compounds discussed here, thirtynine are from the first report of their occurrence. The present study reports 96 compounds obtained from 34 endophytic fungi out of which 15 fungi belonging to 13 genera of Ascomycetes produced 44 compounds, 14 fungi belonging to 5 genera of hyphomycetes yielded 33 compounds and 6 fungi belonging to 2 genera of Coelomycetes yielded 19 compounds. The antioxidant potency of these compounds against different free radicals is briefly described and some details such as host organisms, plant sources, place of collection and the antioxidant properties of these compounds are tabulated in this review. Conclusion: Some of these free radical scavengers have shown wide applications in the food and pharmaceutical industry as potential food preservatives, nutraceuticals, antibacterial, anticancer and antifungal agents. This review aims at highlighting some of the novel compounds isolated recently from endophytic fungi, and their applications as potential antioxidant candidates.

Background: It is always thought that traditional herbal drugs are safe, effective and economical and are used worldwide for healing purposes. Aegle marmelos, belonging to family Rutaceae, is an important medicinal plant of the indigenous medicine system in India. Despite the study on ethnobotanical uses and the presence of bioactive compounds, there was only a handful of research on A. marmelos. The therapeutic use of bioactive compounds is not explored properly. Objective: The objective of this study is to provide comprehensive data on the botanical description, ethnobotany, isolated bioactive compounds and their therapeutic effects according to the pharmacology of A. marmelos and its future prospects for further scientific investigation for the development of effective bioactive compounds. Methods: Literature searches were performed in various databases, such as PubMed, SciFinder and Google Scholar, for peer-reviewed research literature pertaining to the bioactive compounds present and distinctive pharmacological activities of A. marmelos. Results: The literature review indicates that different parts of A. marmelos possess various ethnobotanical uses. A large number of bioactive compounds isolated from different parts of the plant were reviewed which mainly belong to alkaloids, terpenoids, steroids, coumarins, flavonoids and carbohydrate in nature. The plant also possesses a wide range of pharmacological activities, such as antidiarrheal, antimicrobial, anticancer, hepatoprotective, antifertility, anti-inflammatory, wound healing, radioprotective, hypoglycemic and cardioprotective activity. Conclusion: It is clearly proven that different parts of A. marmelos possess numerous therapeutic effects for treating various ailments of human beings. As the scientists anticipated to develop new drugs from natural sources, investigation of modern drugs from A. marmelos should be emphasized. Still, extensive research studies are required on A. marmelos as it is the most important plant of the indigenous medicine system in India. Therefore, this review could be used as a good source of information for researchers who wish to proceed their exploration of A. marmelos.

Background: Since its inception, people are using herbal extracts as natural remedies for the treatment of various diseases. Bryophyllum pinnatum, also known as the air plant, is a well-recognized herb used in folk medicine. It is native to Madagascar and further planted in tropical and subtropical areas around the world. It is known for the profusion of miniature plantlets which arise from the margins of phylloclade. Objective: The aim of this review is to provide the information regarding local and traditional uses, pharmacological activities and different phytochemicals reported from leaves extracts of Bryophyllum pinnatum. Methods: This review article contains a detailed survey of the literature about Bryophyllum pinnatum available in different online databases, such as; PubMed, Web of Science, Science Direct, Elsevier, and Google Scholar, etc. In this review, authors have focused on ethnopharmacological importance and phytochemicals present in Bryophyllum pinnatum and their structure. The structures of the phytochemical were prepared by the ChemDraw tool. Results: This plant is used as a traditional herbal medicine around the globe due to medicinal properties like; anthelmintic, immunosuppressive, hepatoprotective, antinociceptive, anti-inflammatory, antidiabetic, nephroprotective, antioxidant, antimicrobial, analgesic, anticonvulsant and antipyretic. Phytochemical analysis revealed the presence of many bioactive compounds like; alkaloids, flavonoids, triterpenes, steroids, glycosides, bufadienolides, lipids, and organic acids, etc. which are associated with different medicinal properties. Conclusion: Bryophyllum pinnatum possesses diverse pharmacological importance and remarkable medicinal properties. Investigators have reported a large number of phytochemicals exhibiting different medicinal properties and correlation of medicinal properties.

Coumarins are a set of polyphenolic compounds isolated from plant product tonka bean, coumarou in 1820. They belong to the family of benzopyrones, which includes benzene ring joined with the aid of a pyrone ring. Coumarins have attracted great attention of medicinal chemists and pharmacologists in recent years as they been confirmed to bear diverse pharmacological activities like antiinflammatory and analgesic, anti oxidant, anticancer, etc. This review highlights the method of preparation, chemical reactivity, and organic properties such as anti-inflammatory, anticoagulant, antioxidant, anticancer and analgesic activities, of coumarins and their analogues.

Background: Melanoma is a highly aggressive form of skin cancer and is responsible for the majority of the deaths related to this pathology. Recently, different studies have identified naturally occurring compounds of fruits with chemopreventive action. This systematic review aims to investigate the protective role of fruit phytochemicals against melanoma skin cancer from in vitro studies. Methods: The articles were selected using the search terms string "skin neoplasms" OR “melanoma” AND “fruit” in the following databases: Pubmed/Medline, Bireme, Web of Science and ScienceDirect. Results: Out of an initial database search of 391 titles and/or abstracts, 115 full-text articles were eligible and after final evaluation 49 were selected for further assessment. Almost all analysed articles reveal that compounds of different classes (alkaloid, alkane, benzopyrone, cyclopenta[b]benzofuran, ester, flavonoid, tocotrienols, phenolic, phenylpropanoid, phloroglucinol derivative, terpenoids and betalain) possess anti-melanoma in vitro activity. The benzopyrone (α-mangostin) and stilbene (resveratrol) were effective in inhibiting melanoma cell metastasis, essential to stop the progression of malignant cells. Conclusion: Phytochemicals that possess anticancer properties are present in both, common and exotic fruits. Some of these novel compounds are considered as promising starting points for the discovery of effective new drugs.

Background: Currently, a study on the relationship between candidiasis and cancer has been conducted. Until recent years, the opportunistic fungus C. albicans is mainly associated with cancer processes and is able to stimulate carcinogenesis and metastasis. Methods: A number of ionic liquids as potential anticancer and anti-Candida agents have been investigated based on modern theoretical and experimental data about the relationship between oncopathology and candida infection. Results: The analysis of the received experimental results demonstrates that ionic liquid with alkyl chain length of 6 carbon atoms (C6) has not shown anti-Candida activity. The indicators of its cytotoxicity IC50 (28,617μM) and MTC (9,050 μM) against HEP-2 tumor cell line were also very low. Compounds with alkyl chain length C12 have shown high potential of anti-Candida activity and anticancer properties. Conclusion: Based on the obtained results, compound 4 (C12C1IM-Cl) is proposed for further study as a potential double-acting agent with high anticancer and anti-Candida activities. N-myristoyltransferase is presented and used for docking as a potential molecular target responsible for the dual anti-Candida and anticancer activities of studied ionic liquids.

Background: Glycyrrhizic Acid (GA) is the major triterpene saponin of licorice roots. The most important derivative of GA is its monoammonium salt (glycyram, GC). Some pharmacological properties of triterpene saponins explain their molecular complexation with Cholesterol (Chol). However, the molecular complexation of GC with Chol has not been proven. The functional groups of GA and GC involved in the interactions with Chol were not identified. Methods: The complexation has been investigated by the method of isomolar series in the spectrophotometric version, IR, and 13C NMR spectroscopy. The constant is calculated on the basis of isomolar curves. Results: The molecular complex of GC with Chol has been prepared for the first time. It has been shown that GC forms a 1 : 1 complex with Chol having a stability constant Ks of (3.3 ± 0.2)x10⁵ (mol/L)-1 (in 70% aqueous EtOH at 18 °C). Conclusion: Intermolecular interaction in the complex is carried out by hydrogen bond formation between C=O group of GC (in carboxyl group of the terminal residue of glucuronic acid in the carbohydrate part) and 3β-hydroxyl group of Chol: -C=O...H-O-. Hydrophobic contacts of the aglycone part of GC with a lipophilic Chol molecule are possible.

Background: Polyalthia longifolia which originates from India is rich with various useful phytochemicals which are valuable for human health. Accordingly, the current study was conducted to evaluate the combinational antimicrobial activity of P. longifolia Ethyl Acetate Fraction (PLEAF) with ampicillin, antioxidant and cytotoxicity activities. Methods: The evaluation of the synergistic activity of PLEAF fraction and ampicillin against MRSA local isolate was conducted with various antimicrobial assays. Results: The Minimum Inhibitory Concentration (MIC) values of PLEAF fraction (62.5 μg/mL) and ampicillin (5000 μg/mL) were found to decrease to 15.63 μg/mL for PLEAF and 2500 μg/mL for ampicillin respectively in the Fractional Inhibitory Concentration (FIC) assay against the MRSA bacteria. The 2,2-diphenyl1-picrylhydrazyl (DPPH) and nitric oxide free radical scavenging activities showed that PLEAF fraction possessed high antioxidant activity and the combinational of PLEAF fraction and ampicillin exhibited moderate antioxidant activity. The total phenolic content (TPC) of PLEAF was 168.22 ± 0.00407 μg GAE/g of PLEAF fraction. Discussion: Phenolic compounds might be responsible for the observed antioxidant and antimicrobial activity of PLEAF fraction. In addition, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity test against Vero cells the PLEAF fraction was proven to be non-toxic (98.14% of cell viability) and the combination of PLEAF fraction and ampicillin treatment against the Vero cells showed an improved cell viability (52.44%) as compared with ampicillin alone in the treated group. Conclusion: The PLEAF fraction works well in combination with ampicillin to kill the MRSA local resistance strain. PLEAF fraction also showed favourable antioxidant activity and improved Vero cell viability in the presence of ampicillin which is an important attribute of PLEAF fraction to be used in the future combinational therapy.

Background: Meso-tetra-4-actophenyl-porphyrin (TAcPPH2) was synthesized by reacting 4- acetyl-benzaldehyde with pyrrole in propionic acid, and used as a ligand for the synthesis of palladium (II) complex (PdTAcPP). The structure of the ligand and the complex were characterized by NMR and electronic spectroscopy. Methods: The antioxidant activity and the binding parameters of both the ligand and its complex with superoxide anion radical . (O2 -) were measured using cyclic voltammetry based assay. The assays were based on the measurement of the anodic peak current density of . O2− electrochemically generated by reduction of molecular oxygen in DMF. Results: The complex PdTAcPP showed the highest antioxidant activity (0.73 ± 0.01 mg/mL) which is four times higher than that of the standard antioxidant α-tocopherol (3.04 ± 0.03 mg/mL). Discussion: Binding parameters like binding constants, the ratio of binding constants and binding free energies were also measured. Conclusions: The value of the binding free energy ranging from -7.89 kJmol-1 for TAcPPH2 to -17.59 kJ.mol-1for PdTAcPP suggests an electrostatic interaction of . O2− with TAcPPH2 and PdTAcPP which has been found to be the dominant interaction mode. The kinetics of the interaction reaction of the ligand and complex was quantified having second-order rate constant values equal to 0.2 and 1.3 M-1 s-1, respectively.

Background: Ellagic Acid (EA) is a polyphenolic compound that is classified in the natural antioxidants group. Polyphenolic compounds that exert antioxidant activity possess particular importance for scientists, food producers and consumers due to their positive effects on human health. However, despite considerable evidence that EA shows antigenotoxic activity by binding to DNA, there is no systematic genotoxicity study of this substance, which can covalently bind to DNA. This study aims to reveal the possible genotoxic activity of EA using widely accepted assays for the assessment of DNA clastogenic activity: sister chromatid exchange, chromosome aberration, micronucleus and comet assays as well as to predict the interactions among EA and DNA through molecular docking. Methods: Different assays were carried out to identify the clastogenic activity of EA on human lymphocyte DNA using Sister Chromatid Exchange (SCE), Chromosome Aberration (CA), Micronucleus (MN) and single-cell gel electrophoresis (SCGE/comet) assays. For this aim, human peripheral blood lymphocytes were treated with EA (60, 80 and 100 μg/ml) for 24 and 48 hrs in the SCE, CA and MN assays and for 1 hr in the comet assay. Furthermore, molecular docking experiments were also performed to calculate the binding energy of EA on human B-DNA structure (B-DNA dodecamer) as well as to predict noncovalent interactions among these macromolecules. Results: At the concentrations and treatment times (24- or 48-hr) tested, EA did not induce either SCE or Chromosome Aberrations (CAs) as compared to the negative and solvent controls. Although EA slightly increased the percentage of Micronucleated Binuclear (%MNBN) cells as well as the percentage of Micronucleus (%MN) in 24 or 48-hr treatment periods at all concentrations, this increase was not statistically significant as compared to both controls. The effect of EA on DNA replication (nuclear division) was determined by the Proliferation Index (PI), the Nuclear Division Index (NDI) and the Mitotic Index (MI). No statistically significant differences were observed in the PI or NDI in 24- or 48-hr treatment periods in human lymphocyte cultures treated with EA at various concentrations. EA generally had no significant effect on the MI, as observed with the PI and NDI. Discussion: Although the concentrations of 60 and 80 μg/mL at a 24-hr treatment period and the concentrations of 60 μg/mL and 100 μg/mL at 48-hr treatment period generally decreased the MI, those decreases were not statistically significant when compared to negative and solvent controls. Moreover, none of the concentrations of EA tested in this study were able to increase DNA damage determined by the tail DNA length, %DNA in tail and tail moment parameters in the comet assay. Although the amount of DNA damage in the comet assay decreased with increasing concentrations of EA, this decrease was not statistically significant as compared to both controls. However, molecular docking experiments interestingly showed that the binding free energy of EA with B-DNA was -7.84 kcal/mol-1, indicating a strong interaction between the two molecules. Conclusion: Although the findings of our study show that EA does not have genotoxic potential in human chromosomes, molecular docking experiments revealed strong hydrogen bonding between EA and B-DNA molecules. Therefore, it has been proposed that the prevailing information suggesting that the molecules that bind to DNA cause genotoxic effects should be reconsidered from a wider perspective.

Background: Aspergillus Versicolor is a marine-derived fungus isolated from Hyrtios Erectus Red Sea sponge. Methods: The aim of this study was to carry out a pharmacological screening and investigation for the in vitro biological activity (antioxidant, cholinergic, antidiabetic and anticancer) of Aspergillus Versicolor crude extract’s active compounds by using different qualitative and quantitative methods. Results: The present study results showed that Aspergillus Versicolor crude extracts contain 0.6 mg total phenolic/mg crude extract. Aspergillus Versicolor also showed a potent antioxidative capacity by decreasing the oxidation of ABTS. The anticancer and inhibitory effects of Aspergillus Versicolor crude extracts on PTK and SHKI were found to be 75.29 % and 80.76%; respectively. The AChE inhibitory assay revealed that Aspergillus Versicolor extracts had an inhibitory percentage of 86.67%. Furthermore, the anti-inflammatory activity using COX1, COX2, TNF, and IL6 was 77.32, 85.21 %, 59.83%, and 56.15%; respectively. Additionally, the anti-viral effect using reverse transcriptase enzyme showed high antiviral activity with 92.10 %. Conclusion: The current study confirmed that the Aspergillus versicolor crude extract and its active constituents showed strong effects on diminishing the oxidative stress, neurodegenerative damage, antiinflammatory, anti-cancer and anti-viral, suggesting their beneficial role as a promising fermented product in the treatment of cancer, oxidative stress, Alzheimer's, anti-inflammatory and anti-viral diseases.

Background: Motivated by the need for bioprospecting new drug studies have revealed a variety of secondary metabolites with biological activity. In particular, antimicrobial research confronts the growing reality of resistance of microorganisms to currently available drugs. Modifications in the chemical structure of secondary metabolites may be important in the development of a product to improve the efficacy of these compounds. Being cognizant of the fact that modifications in the chemical structure could enhance the biological activity and improve the compound characteristics for the development of a product, the present study aimed to verify, if there is the possibility of a significant difference in the bioactivity of verbanol in relation to verbenol. Methods: The biological activity was evaluated by agar diffusion assay and microdilution. Results: Verbanol is a bioactive secondary metabolite produced by the endophytic fungus Diaporthe terebinthifolli LGMF658. This compound has bactericidal activity against Staphylococcus aureus and fungicide against Candida albicans according to the microdilution assay. Discussion: In contrast, verbenol, a byproduct of verbanol, did not control the development of the bacterium and showed fungistatic activity against yeast. Conclusion: The results demonstrated that the presence of the double bond, which increased the polarity of the compound, reduced its bioactivity, corroborating with other studies that report the importance of lipophilicity for antimicrobial action.

Background: The assessment of underexploited leaves has become crucial to supplement the rapidly depleting sources of bioactive components as well as provide available nutrient sources for local inhabitants. Methods: This study thus investigated the bioactive components of the oil, and fatty acid composition, free radical scavenging potentials, and protein qualities of leaves of Z. mays and G. celosioides using standard methods. The bioactive components of the oils and fatty acids were determined by Gas Chromatograpy, while the amino acid and in-vitro antioxidant potentials were determined using a Technicon Sequential Multi-Sample (TSM) Amino Acid Analyzer, and spectrophotometer, respectively. Results: The Z. Mays leaves showed the abundance of farnesene, hexadecanoic acids, and caryophellene while G. celosioides produced high level of octadecadienoic acid, hexadecanoic acid, and phytol. Z. mays and G. celosioides contained 72.48% and 60.55% unsaturated fatty acids respectively, with the abundance of linolenic acid for Z. mays and oleic acid for G. celosioides. The result for the in vitro antioxidant % inhibition showed a concentration dependent free radical scavenging potentials of the leaves. Both G. celosioides and Z. mays produced greater 1,1-diphenyl-2- picrylhydrazyl (DPPH), and hydrogen peroxide radical scavenging potentials than ascorbic acid, while at 40ppm the nitric oxide and 2,2- azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical % inhibition of Z. mays leaves were lower than those for ascorbic acid. Discussion: The number of essential amino acids in both plants were 48.20 and 39.25 g/100g, total branched chain amino acids (TBCAA) were 21.15 and 16.92 g/100g, predicted protein efficiency ratios (P-PERs) were in the range of 3.02-3.23 and 2.68-2.77, and the essential amino acid index (EAAI) were 1.52 and 1.48, for Z. mays and G. celosioides leaves respectively. Conclusion: From these results, the utilization of Z. mays and G. celosioides for high quality protein, unsaturated fatty acids and potent antioxidant sources, should be massively encouraged.

Introduction: Cancer is still an untreatable disease and the second leading cause of death globally. The heterocyclic compounds have always played a major role in the anticancer drug discovery program. 1,2,4-Triazine-6-ones is a heterocyclic privileged structure with diversified activities. In the presented study, 21 novel 2,5-disubstituted-3-phenyl-1,2-dihydro-1,2,4-triazin-6 (5H)-one derivatives (13(a-k), 18(a-j) and 21(a1-a4, b)) have been synthesized and tested for their anticancer activity. Methods: The 2,5-disubstituted-3-phenyl-1,2-dihydro-1,2,4-triazin-6(5H)-one derivatives (13(a-k), 18(a-j) and 21(a1-a4, b) were synthesized by refluxing substituted-2-phenyloxazol-5(4H)-one and hydrazine derivatives. Substituted aldehydes were synthesized via Vilsmeier-Haack reaction, while substituted- 2-phenyloxazol-5(4H)-one derivatives were synthesized by Erlenmeyer Plochl azlactone synthesis. Twenty-one compounds were selected and screened at the National Cancer Institute (NCI), USA, for anticancer activity at a single high dose (10-5M) in full NCI 60 cell panel assay. Results and Conclusion: The selected compounds (13a, 13b, 13c, 13f, 13h, 13i, 13j, 18h, 18i, 21a4) were found to be active against different cancer cell lines. The compound, 5-((5-chloro-3-methyl-1- phenyl-1H-pyrazol-4-yl)methylene)-2-(4-nitrobenzoyl)-3-phenyl-1,2-dihydro-1,2,4-triazin-6(5H)-one (13a) was found to be a potent anti-cancer agent as electron-rich moiety on phenyl at position 2 of triazine nucleus, having a great impact on anticancer activity.