Current Bioactive Compounds - Volume 16, Issue 3, 2020

Background: Molecular docking is probably the most popular and profitable approach in computer-aided drug design, being the staple technique for predicting the binding mode of bioactive compounds and for performing receptor-based virtual screening studies. The growing attention received by docking, as well as the need for improving its reliability in pose prediction and virtual screening performance, has led to the development of a wide plethora of new docking algorithms and scoring functions. Nevertheless, it is unlikely to identify a single procedure outperforming the other ones in terms of reliability and accuracy or demonstrating to be generally suitable for all kinds of protein targets. Methods: In this context, consensus docking approaches are taking hold in computer-aided drug design. These computational protocols consist in docking ligands using multiple docking methods and then comparing the binding poses predicted for the same ligand by the different methods. This analysis is usually carried out calculating the root-mean-square deviation among the different docking results obtained for each ligand, in order to identify the number of docking methods producing the same binding pose. Results: The consensus docking approaches demonstrated to improve the quality of docking and virtual screening results compared to the single docking methods. From a qualitative point of view, the improvement in pose prediction accuracy was obtained by prioritizing ligand binding poses produced by a high number of docking methods, whereas with regards to virtual screening studies, high hit rates were obtained by prioritizing the compounds showing a high level of pose consensus. Conclusion: In this review, we provide an overview of the results obtained from the performance assessment of various consensus docking protocols and we illustrate successful case studies where consensus docking has been applied in virtual screening studies.

Background: Plant-based products and their derivatives have been widely used in the medicine, nutraceuticals, and the cosmetic and pharmaceutical field for a very long time. A large number of important drugs of modern medicine have also been derived from the plant's sources. Plant products specifically the pure phytochemical also known as ‘biomarkers’ have been used in the food and pharmaceutical industries. Biomarker compounds are pure phytochemical and they are mainly responsible for various pharmacological activities of plant material and examples of biomarker are Amarogentin, Vasicine, Hyoscyamine and Paclitaxel. Methods: Various literature databases were searched to collect important information about Amarogentin in this review. Ethnomedicinal uses, pharmacological activities, phytochemical aspects and modern analytical tools of amarogentin were presented and discussed. Further, all the collected information’s were categorized into different section as per the need of the manuscripts. Moreover, data were also presented in the graphical abstract, Figures and Table section too. Results: Swertia chirata (S. chirata) is a common plant of Gentianaecae family which is mainly known for their bitter taste. Gentiopicroside, amarogentin, swertiamarin, isovitexin and isogentisin are some important phytoconstituents of S. chirata. Decoction, infusion, pastes and juice of S. chirata are basically used in the medicine. Various Pharmacological activities such as hypoglycemic, antimicrobial, antimalarial, antihepatotoxic, anticarcinogenic, antioxidative and anti-inflammatory have been reported in the literature for S. chirata plant. Amarogentin, a bitter secoiridoid glycoside of S. chirata has been well known for antibacterial, anticholinergic anti-lieshmanial, chemopreventive, antihepatitis and anticancer activities. Conclusion: Information provided in the present paper regarding phytochemistry, pharmacological uses and analytical aspects including bioavailability will be beneficial to various disciplines of biological science. Development of plant tissue culture-based approaches is also needed for the proper conservation of S. chirayita plants in the future.

Background: The variety of biological applications of vanadium impressed researchers to develop vanadium based drugs. The most well-known fact of vanadium is that it is necessary for human beings as an insulin-enhancing agent and herein, we mainly provide an overview of vanadium-based drugs and their applications in the medicinal field for the treatment of diseases such as diabetes and cancer. The first part of this review is focused on mechanistic studies involved in the anti-diabetic activity. The latter part explains the use of vanadium and its related coordination compounds in the treatment of cancer. Methods: This review is purely based on literature search available in the database. We focused on the reports available on the recent advancements in the vanadium chemistry and its biological properties, mainly anti-diabetic and anticancer activities of vanadium based compounds. Results: The study of clinical trials of vanadium and its drug molecules imposed more demand due to their remarkable activity with less toxicity. Conclusion: A brief literature survey was made pertaining to the applications of vanadium compounds/ complexes. Particularly, special attention was paid to explaining mechanistic studies of vanadium based compounds in the treatment of diabetes and cancer.

Background: Valerian extract is widely used in dietary supplements as well as in conventional, traditional and alternative medicines. It is one of the most used herbal plants for the treatment of several disorders, mainly related to the digestive and the nervous systems. Dozens of chemical constituents with pharmacological and therapeutic properties were identified in essential oils and/or other extracts of valerian’s roots, rhizomes and aerial parts. This review summarizes and updates the current knowledge about the pharmacological properties of valerian, highlighting the most recent clinical, in vitro and in vivo findings, and intends to identify and propose future directions for further research regarding the effective biological effects of Valeriana spp. Methods: This review analyzed the scientific literature published in PubMed, Science Direct and Web of Science. Results: Some reports are contradictory or inconclusive, probably due to the presence of chemically distinct chemotypes within a species of Valeriana or to different approaches adopted in different studies. Also, there are a number of studies showing that co-administration of herbal supplements and drugs may promote pharmacokinetic and pharmacodynamic herb-drug interactions. Conclusion: It is of utmost importance to clarify the state of the art related to Valeriana spp. therapeutic properties and their effects on metabolism.

Background: There is much epidemiological evidence that fruits, vegetables, medicinal plants, and their phytochemicals could lower the progression and development of various forms of cancer. The plants are active reservoirs for novel chemical entities and provide a promising resource for the management of cancer. Methods: Several analyses have signified that bioactive flavonoids and phenolic acids might be widely practiced for the management as well as therapy of numerous carcinomas. A large number of research works are now focusing on natural polyphenolic compounds and trying to find out new and more effective treatment strategies for cancer patients. Results: The probable mechanism comprises anti-oxidant, anti-inflammation, apoptosis and induces inhibition of cell proliferation along with genomic phenomena elaborated in cancer therapy. Conclusion: In the last five years, studies investigated the antitumor potential of common polyphenolic groups (phenolic acids, flavonoids, lignins, resveratrol, stilbene, quercetin etc.) exploring the prospective mechanism, based on epidemiological data thus reporting therapeutic evidence and various clinical examinations.

Background: Reactive oxygen species and reactive nitrogen species, which are collectively called reactive oxygen nitrogen species, are inevitable by-products of cellular metabolic redox reactions, such as oxidative phosphorylation in the mitochondrial respiratory chain, phagocytosis, reactions of biotransformation of exogenous and endogenous substrata in endoplasmic reticulum, eicosanoid synthesis, and redox reactions in the presence of metal with variable valence. Among medicinal plants there is a growing interest in Crocus sativus L. It is a perennial, stemless herb, belonging to Iridaceae family, cultivated in various countries such as Greece, Italy, Spain, Israel, Morocco, Turkey, Iran, India, China, Egypt and Mexico. Objectives: The present study aims to address the anti-toxicant role of Crocus sativus L. in the cases of toxin and drug toxification. Materials and Methods: An electronic literature search was conducted by the two authors from 1993 to August 2017. Original articles and systematic reviews (with or without meta-analysis), as well as case reports were selected. Titles and abstracts of papers were screened by a third reviewer to determine whether they met the eligibility criteria, and full texts of the selected articles were retrieved. Results: The authors focused on literature concerning the role of Crocus Sativus L. as an anti-toxicant agent. Literature review showed that Saffron is a potent anti-toxicant agent with a plethora of applications ranging from anti-oxidant properties, to chemotherapy protective effects. Conclusion: Literature findings represented in current review herald promising results for using Crocus Sativus L. and/or its active constituents as anti-toxicant, chemotherapy-induced protection and toxin protection.

Background: Garcinielliptone FC corresponds to a polyprenylated acylphloroglucinol having a benzophenonic core (diphenylmethanone) substituted with isoprenyl(s) group(s) (3-methyl-2-butenyl) and 2-isopropenyl-hex-5-enyl. Objectives: The present work evaluated the antioxidant activity of garcinielliptone FC (GFC) in vitro against non-biological radicals [2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS•+)] and ex vivo against oxidative damage induced by AAPH (2,2'-azobis-2-methylpropionamidine dihydrochloride) and iron/citrate ion in erythrocytes and mitochondria, respectively. Methods: In addition to the protective effect, the main biochemical indexes of oxidative stress, such as lipid peroxidation through the formation of Thiobarbituric Acid Reactive Substances (TBARS), Superoxide Dismutase (SOD), Catalase (CAT) activity and reduced glutathione (GSH) levels. Results: According to the results obtained in erythrocytes, the antioxidant results at concentrations of 0.1, 0.3, 0.7, 1.5 and 3.0 mM were 26.34 ± 0.68, 43.39 ± 2.17, 62.27 ± 2.17, 86.69 ± 0.47 and 92.89 ± 0.45%, respectively, where GFC reduced the rate of oxidative hemolysis when compared to AAPH (p<0.05). The antioxidant activity observed in erythrocytes was also seen in mitochondria in which GFC reduced mitochondrial swelling by increasing the absorbance when compared to iron/citrate ion complex (p<0.05). In both biological models, GFC had an antioxidant effect on erythrocyte and mitochondrial redox balance when analyzing oxidative stress biomarkers, such as reduction of lipid peroxidation and inhibition of depletion in the activity of SOD, CAT and GSH levels. Conclusion: In conclusion, GFC had in vitro and ex vivo antioxidant activity against oxidative damage induced in erythrocytes and mitochondria acting on the erythrocytic and mitochondrial redox balance.

Background: A series of 1-(2-(2-amino-5-carbamoyl-6-(1-(substitutedphenyl) prop-1-enyl) pyrimidin-4-yloxy)acetyl) semicarbazide (4a-i) derivatives was synthesized from substituted aromatic aldehydes, ethyl cyanoacetate and guanidine hydrochloride and characterized by analytical and spectral data, FTIR, 1H-NMR and Mass spectroscopy data. Methods: The antiTB action of the synthesized compounds was screened in comparison with the standard drug Rifampicin using MABA assay method. The SAR of substituted aromatic aldehydes with modification at ortho, meta and para positions with electron withdrawing group. Result: The compounds 1-(2-(2-amino-5- carbamoyl-6-(1-(2-fluorophenyl) prop-1-enyl) pyrimidin-4- yloxy) acetyl) semicarbazide and 1-(2-(2-amino- 5-carbamoyl-6-(1-(3-chlorophenyl) prop-1-enyl) pyrimidin-4-yloxy) acetyl) semicarbazide showed equal MIC values against Mycobacterium tuberculosis H37Ra with the value of 3.90μg/ml. Conclusion: The SAR study revealed that the antiTB activity of the synthesized compounds were affected by lipophilicity of the substituent.

Background: In the present study, a bioguided fractionation was realized to isolate bioactive compounds on Fusarium oxysporum f.sp. albedinis (Foa) from Citrullus colocynthis L. Foa is the causal agent of “ Bayoud”, a lethal disease of date palm. Methods: Extracts of Citrullus colocynthis fruits peels using four solvents (n-hexane, dichloromethane, ethanol, chloroform) were tested for antifungal effect on Foa with radial growth technique. The ethanolic extract was selected for fractionation to isolate bioactive compounds (Percentage of Growth Reduction “PGR”: 63.6%). The fractionation was realized using six solvents (hexane, dichloromethane, ethyl acetate, methanol, butanol, water). Through fractionation, methanolic and butanolic fractions (PGR= 57.6% and 69.7%, respectively) had been chosen for bioactive compounds isolation. Results: Chromatographic and spectroscopic analyses had led to isolation of six compounds deduced as: (C1): 2-O-β-D-glucopyranosylcucurbitacin E; (C2): 2-(Nonan-8-one)-(1H)-4-quinolone; (C3): 2- (Nonan-8-one) 4-methoxy-quinoline, (C4): Isosaponarin; (C5): Isovitexin; (C6): Isoorientin 3’-Omethyl ether. The isolated compounds had been tested for antifungal effect. The compound (C1) represents the best effect among isolated compounds (PGR, up to 54.5%). Conclusion: The efficiency of (C1) reflects its opportunity to be used for the development of efficient treatment against Bayoud disease.

Background: Desert truffles (Terfezia species) are known by their vital nutritional benefits as they are considered as rich sources of vitamins, fatty acid, minerals and proteins. Methods: The chemical constituents of the different solvent extracts of Terfezia species were isolated and identified by column chromatography, spectroscopic and GC-MS analyses. Also, the ethyl acetate and acetone extracts of different fungal isolates, associated Terfezia, after grown on rice medium were screened for their antimicrobial, anticancer and antioxidant activities via disc agar plate, micro culture tetrazolium (MTT) and 2,2-azino-di-[3-ethylbenzo-thiazolin-sulphonate] (ABTS) assays, respectively. The promising fugal strains were molecularly identified by 18SrRNA tool. Results: Bio-guided separation of methylene chloride, ethyl acetate and n-butanol fractions of Terfezia species led to identification of nine compounds namely; (R)-4,8-dihydroxy-7-hydroxymethyl-6- methoxy isochroman-1-one (1), 4-deoxy-4α-phorbal-12-(2,3-dimethyl)butyrate-13-isobutyrate (2), oxyphylline B (3), terfezien A (4), latilagascene D (5), amaiouine (6), senbusine acetate (7), terfezien B (8) and marinoquinoline D (9). Moreover, sixteen compounds were identified in the n-hexane extract via GC-MS analysis, accounting for 93.69% of the total detected components in the extract. While, twenty five components were detected in the methylene chloride extract, representing 43.86% from total detected components in the extract. Eight fungal strains were isolated from Terfezia sp., powder by serial dilution methods and these fungi were cultivated on solid rice medium. Also, their ethyl acetate and acetone extracts were subjected to biological studies including antimicrobial, antioxidant and anticancer activities. The three potent fungal strains (1M, 4M and 8M) were identified by the molecular technique 18SrRNA as Aspergillus niger 1M-EGY-IQ, Penicillium crustosum 4M-EGY-IQ, and Fusarium proliferatum 8M-EGY-IQ for 1M, 4M and 8M, respectively. Conclusion: Terfezia sp., comprise a rich source of bioactive compounds and could be considered as an interesting candidate for the treatment of infectious diseases.

Background: Codium intricatum, locally known as Pukpuklo, is a seasonal and edible green alga found in Ilocos Norte, Philippines. In this study, the biochemical content, cytotoxic and inhibitory potential against Matrix Metalloproteinase-1 (MMP-1) production of the polysaccharide-protein fractions from C. intricatum is first reported. MMPs are novel targets for therapeutic intervention with the potential to inhibit tumor growth, metastasis and invasion either on their own or in conjunction with cytotoxic treatments. Methods: Water-soluble Crude Polysaccharide (CP) and its fractions (CFs) from C. intricatum were isolated using hot water and ion-exchange chromatography and analyzed using different analytical techniques. Cytotoxicity against MCF-7 breast cancer cells and Human normal Dermal Fibroblasts (HnDFs) was determined by MTT assay. The MMP-1 inhibitory potential was tested in UVB exposed Human normal Dermal Fibroblast Cells. Results: CP and CFs afforded carbohydrates (2.07-16.1%), sulfates (1.81%- 9.9%), protein (0.05-2.7%), ash (<77.2%), lipids (<1.0%) and uronic acid (0.15- 4.49%). FT- IR and NMR spectra of CP and CFs exhibited absorption peaks comparable to sulfated galactans. Both CP and CFs significantly inhibited the growth of breast cancer (MCF-7) in a concentration-dependent manner (p<0.05), induced proliferation of HnDFs, inhibited the production of Matrix metalloproteinase-1 (MMP-1) in UV-B induced HnDFs (p<0.05). Conclusion: Results are highly suggestive that polysaccharide fractions from C. intricatum are bioactive molecules with cytotoxic and anti-metastasis potential.

Background: Salix gilgiana is a deciduous tree that grows in northern Japan, the Korean peninsula, eastern Russia along the Ussuri River, and northeast China. The stem of this tree is dried and consumed orally as a folk medicine. Our intensive screening of various plant materials found that the MeOH extract of its dried stem exhibited significant antiproliferative activity against HL-60 leukemic cells with an IC50 of 16 ppm. We systematically investigated the biologically active compounds of the MeOH extract of the dried stem of S. gilgiana. Methods: The MeOH extract of S. gilgiana dried stem was fractionated by a repeated chromatography monitored by antiproliferative activity against HL-60 leukemic cells. Five active compounds were isolated and the structures were elucidated by MS, 1H- and 13C-NMR spectroscopy, and X-ray analysis. Results: The active compounds were identified as 7-ketositosterol (I), 7β-hydroxysitosterol (II), 7α- hydroxysitosterol (III), (4-hydroxyphenyl)ethanol (IV), and (4-hydroxyphenyl)propan-1-ol (V). The strongest activity was found for 7α-hydroxysitosterol (III), with an IC50 of 8.4 μM. This is the first report of the isolation of these compounds from S. gilgiana. Conclusion: Five compounds were isolated by a repeated chromatography under the guidance of antiproliferative bioassay using HL-60. The structures were identified as three β-sitosterol oxides and two phenolic compounds. Since Salix species, namely, willow trees, have beneficial characteristics including rapid growth, easy cloning, and resistance to high humidity and dryness, they may be utilized as a relatively inexpensive tool for the efficient production of useful bioactive materials.

Background: Flueggea leucopyrus Willd. leaf has been used since ancient time for its sex enhancing activity by traditional physicians. So, the work was chosen to authenticate the knowledge of pharmaceutical significance of the plant. Methods: The dried leaves of Flueggea leucopyrus were extracted by cold maceration method using water. Aqueous extract of Flueggea leucopyrus leaf was screened for phytochemicals and in vivo aphrodisiac activity using mating behavior, potency and morphological tests. Results: Qualitative phytochemical analysis of leaves of Flueggea leucopyrus showed the presence of alkaloids, terpenoids, unsaturated sterols, glycosides, saponins, phenolics, flavonoids, tannins, carbohydrates and protein. Results revealed that all the treated groups on the 15th, 30th and 45th day of treatment showed significant increase in Intromission Frequency, Mounting Frequency and Ejaculatory Latency significant decrease in Intromission Latency, Mounting Latency, Inter Intromission Interval and Post Ejaculatory Interval. In Test for Potency significant increase in Erections, Long Flips and Quick Flips were observed. Morphological study showed significant increase in reproductive organs weight and Sperm Count in all the experimental animals. Conclusion: The prolonged treatments for all the treated groups were highly effective to increase the sexual libidity, as compared to the solvent control. This indicates that aphrodisiac activity has been shown by water extract but it is less than the standard used for study.

Background: The objective of this study was to investigate the antiproliferative effect of Stachys sieboldii MIQ. extracts on cancer cell lines. Methods: Dried S. sieboldii MIQ. was extracted using acetone/methylene chloride (A+M) or methanol (MeOH), and then fractionated using n-hexane, 85% aq. methanol (MeOH), butanol (BuOH) and distilled water. The cytotoxic activity of S. sieboldii MIQ. against AGS human gastric, HT-29 human colon and HT-1080 fibroblast cancer cell lines was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Results: The A+M extract showed significantly higher inhibition of cell growth in all three cell lines compared to the MeOH extract (p < 0.05). All the extracts and fractions from S. sieboldii MIQ. decreased the growth of AGS cells, and the effect was concentration-dependent. Among the different fractions, the n-Hexane and 85% aq. MeOH fractions inhibited AGS cell growth by >50% at a concentration of 0.1 mg/mL (p < 0.05). All fractions inhibited the proliferation of HT-29 cancer cell lines (p < 0.05), showing >50% inhibition at a concentration of 0.25 mg/mL. The A+M extract inhibited the growth of the HT-1080 cancer cells by 60% at a concentration of 0.25 mg/mL. The n-Hexane and 85% aq. MeOH fractions showed the highest growth inhibitory effect on the HT-1080 cancer cells (p < 0.05), similar to that observed in the AGS cancer cells. Conclusion: Thus, the n-Hexane and 85% aq. MeOH fractions from S. sieboldii MIQ. likely contain bioactive compounds such as polyphenols and flavonoids that could prevent cancer proliferation. Further research is needed to isolate these important compounds from the extracts.

Background: Novel carboxamides and thioureas of 2,3-dihydro-5,6-dimethoxy-2-((piperidin- 4-yl)methyl) inden-1-one were synthesized and their potential anticholinesterase activities were evaluated. The inhibition potency of the compounds 17a-j and 19a-j against AChE was measured and evaluated using Ellman’s spectrophotometric method. Among carboxamides series, compound 17f, 17i, 17j and among thiourea series, compound 19a, 19b were found to be the most active. Methods: The scaffold 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl) inden-1-one 16, key intermediate of drug donepezil has been synthesised in three steps and derivatised as carboxamides and thioureas for SAR studies. Compounds 17a-j and 19a-j were characterised by 1H NMR and LCMS. The inhibitory activity and antiamnesic effect were studied using different sources such as electric eel AChE, human serum AChE and rat brain homogenate AChE. Results: The results of bioassays indicated that among all the synthesized compounds tested, five compounds 17f, 17i, 17j, 19a and 19b shows IC50 at a dose of 67, 42, 64, 52 and 63 nM respectively against electric eel, human serum and rat brain homogenate, which lead to the suggestion that compound 17i might be considered to be a potent AChE inhibitor. Conclusion: Derivatives of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one with different substitutions were synthesised and tested for their AChE activity. The order of potency is 17i>17j>17f and 19a>19b. The other compounds screened failed to elicit any inhibition of acetyl cholinesterase from rat brain homogenate. It may be concluded from this study that, for effective binding and blocking the AChE activity, molecule needs to bind with peripheral site and active site of the enzyme. Therefore, it can be summarized that by changing the functional group and substitution in the scaffold 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one needs to be studied for better AChE inhibitory activity in future research.

Background: Arctigenin is a lignan found in Arctium lappa L. (Asteraceae) that displays anti-inflammatory activities. Previous studies showed that the crude extract of A. Lappa has antitumor activity in human liver carcinoma, lung and stomach cancer cells. The aim of this study was to obtain arctigenin from A. lappa L., as well as to evaluate its antiproliferative effects in cells of liver carcinoma (HepG2) and fibroblasts (NIH/3T3). Methods: Arctigenin was obtained from the hydrolysis of arctiin, which was isolated from the crude extract of A. lappa. The effects of arctigenin and arctiin on HepG2 cell viability and cell adhesion were analyzed by MTT method. Adhesion assay was also carried out to evaluate the antitumor activity. Results: Our results showed that the analytical process to obtain arctigenin was fast and easy. In vitro experiments showed that arctigenin (107-269 μM) decreased HepG2 cells viability and did not cause cytotoxicity on NIH/3T3 cells. Arctigenin (27-269 μM) demonstrated anti-adhesion in HepG2 cells in a concentration-dependent manner, when compared with control. Conclusion: These results suggest a promising pharmacological activity for arctigenin as an antiproliferative compound.

Background: The marine red alga Plocamium naturally produces halogenated monoterpenes with varied biological activities. In our continuing efforts to discover new lead compounds for the treatment of HIV/AIDS as well as novel antibacterial compounds, various Namibian Plocamium species have been investigated. Methods: A rare but known compound namely 1E,3R,4S,5E,7Z-1-bromo-3,4,8-trichloro-7- (dichloromethyl)-3-methylocta-1,5,7-triene (1) was isolated from a Namibian Plocamium red alga. The anti-HIV activity of compound 1 was investigated against three HIV enzymes namely, HIV protease, reverse transcriptase and integrase. In addition, compound 1 was also screened for antibacterial activity against selected microbes using the disc diffusion method. Results: Compound 1 demonstrated selective in vitro inhibition against HIV-1 integrase with a 50% inhibition concentration of <0.06 mM. Weak inhibitory activity was observed against HIV-1 reverse transcriptase and protease. Compound 1 also showed antibacterial activity against Staphylococcus aureus (ATCC 25923), Alcaligenes faecalis (ATCC 8750) and Serratia marcescens (ATCC 8100) with MIC values of 0.65 mM, and 1.29 mM for Klebsiella pneumonia (ATCC 13883). Conclusion: The results of this study highlight the potential of halogenated monoterpenes from red seaweed as possible leads in the development of new anti-HIV and antimicrobial pharmaceuticals.