Cholinesterase Inhibitory and In Silico Toxicity Assessment of Thirty-Four Isoquinoline Alkaloids - Berberine as the Lead Compound.

BACKGROUND: Cholinesterase (ChE) inhibitors used currently in clinics for the treatment of Alzheimer's disease (AD) are the most prescribed drug class with nitrogen-containing chemical formula. Galanthamine, the latest generation anti-ChE drug, contains an isoquinoline structure. OBJECTIVE: The aim of the current study was to investigate the inhibitory potential of thirty-four isoquinoline alkaloids, e.g. (-)-adlumidine, ß-allocryptopine, berberine, (+)-bicuculline, (-)-bicuculline, (+)-bulbocapnine, (-)-canadine, (±)-chelidimerine, corydaldine, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, dehydrocavidine, (+)-fumariline, (-)-fumarophycine, (+)-α-hydrastine, (+)-isoboldine, 13-methylcolumbamine, (-)-norjuziphine, norsanguinarine, (-)-ophiocarpine, (-)-ophiocarpine-N-oxide, oxocularine, oxosarcocapnine, palmatine, (+)-parfumine, protopine, (+)-reticuline, sanguinarine, (+)-scoulerine, (±)-sibiricine, (±)-sibiricine acetate, (-)-sinactine, and (-)-stylopine isolated from several Fumaria (fumitory) and Corydalis species towards acetyl- (AChE) and butyrylcholinesterase (BChE) by microtiter plate assays. The alkaloids with strong ChE inhibition were proceeded to molecular docking simulations as well as in silico toxicity screening for their mutagenic capacity through VEGA QSAR (AMES test) consensus model and VEGA platform as statistical approaches. The inputs were evaluated in a simplified molecular input-line entry system (SMILES). RESULTS: ChE inhibition assays indicated that the highest AChE inhibition was caused by berberine (IC50: 0.72 ± 0.04 µg/mL), palmatine (IC50: 6.29 ± 0.61 µg/mL), ß-allocryptopine (IC50: 10.62 ± 0.45 µg/mL), (-)-sinactine (IC50: 11.94 ± 0.44 µg/mL), and dehydrocavidine (IC50: 15.01 ± 1.87 µg/mL) as compared to that of galanthamine (IC50: 0.74 ± 0.01 µg/mL), the reference drug with isoquinoline skeleton. Less number of the tested alkaloids exhibited notable BChE inhibition. Among them, berberine (IC50: 7.67 ± 0.36 µg/mL) and (-)-corydalmine (IC50: 7.78 ± 0.38 µg/mL) displayed a stronger inhibition than that of galanthamine (IC50: 12.02 ± 0.25 µg/mL). The mutagenic activity was shown for ß-allocryptopine, (+)- and (-)-bicuculline, (±)-corydalidzine, (-)-corydalmine, (+)-cularicine, (-)-fumarophycine, (-)-norjuziphine, (-)-ophiocarpine-N-oxide, (+)-scoulerine, (-)-sinactine, and (-)-stylopine by means of in silico experiments. The results obtained by molecular docking simulations of berberine, palmatine, and (-)-corydalmine suggested that the estimated free ligand-binding energies of these compounds inside the binding domains of their targets are reasonable to make them capable of establishing strong polar and nonpolar bonds with the atoms of the active site amino acids. CONCLUSION: Our findings revealed that berberine, palmatin, and (-)-corydalmine stand out as the most promising isoquinoline alkaloids in terms of ChE inhibition. Among them, berberine has displayed a robust dual inhibition against both ChEs and could be evaluated further as a lead compound for AD.

A new sesquiterpene, prosoterpene, from Prosopis africana (Guill. & Perr.) Taub.

A new sesquiterpene (Prosoterpene, 1) and eleven reported compounds (2-12) of several classes, such as flavonoids, alkaloids, phenolic acids, and long-chain alcohols, were isolated from the BuOH extract of Prosopis africana (Guill. & Perr.) Taub. Compounds 2-10 were reported for the first time from this plant. Isomers 11 and 12 were separated for the first time. Extensive spectroscopic techniques and literature comparisons were used to characterise their structures. Furthermore, compounds 3, 5-8, and 10-12 were performed for anti-glycation and cytotoxicity activities. Compound 3 (quercetin-3-O-α-L-rhamnoside) exhibited moderate anti-glycation activity. All tested compounds were non-cytotoxic against MCF-7 (breast cancer), NCI-H460 (lung cancer), Hela (cervical cancer), and BJ (normal human fibroblast) cell lines.

Urtica dioica-Derived Phytochemicals for Pharmacological and Therapeutic Applications.

Urtica dioica belongs to the Urticaceae family and is found in many countries around the world. This plant contains a broad range of phytochemicals, such as phenolic compounds, sterols, fatty acids, alkaloids, terpenoids, flavonoids, and lignans, that have been widely reported for their excellent pharmacological activities, including antiviral, antimicrobial, antihelmintic, anticancer, nephroprotective, hepatoprotective, cardioprotective, antiarthritis, antidiabetic, antiendometriosis, antioxidant, anti-inflammatory, and antiaging effects. In this regard, this review highlights fresh insight into the medicinal use, chemical composition, pharmacological properties, and safety profile of U. dioica to guide future works to thoroughly estimate their clinical value.

A new steroidal alkaloid from Fritillaria michailovskyi Fomin.

A new steroidal alkaloid, michainine (1), was isolated from Fritillaria michailovskyi Fomin, along with nine known compounds 2-10 of different classes, including ribonucleoside, steroids, and fatty acids, which were isolated for the first time from this plant. Their structures were elucidated through extensive spectroscopic techniques, as well as by comparing the data in the literature. Furthermore, the dichloromethane fraction of F. michailovskyi showed a positive butyrylcholinesterase inhibitory activity, along with non-cytotoxicity against 3T3 cell line.

Outlining In Vitro and In Silico Cholinesterase Inhibitory Activity of Twenty-Four Natural Products of Various Chemical Classes: Smilagenin, Kokusaginine, and Methyl Rosmarinate as Emboldening Inhibitors.

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.

The Therapeutic Potential of Anthocyanins: Current Approaches Based on Their Molecular Mechanism of Action.

Anthocyanins are natural phenolic pigments with biological activity. They are well-known to have potent antioxidant and antiinflammatory activity, which explains the various biological effects reported for these substances suggesting their antidiabetic and anticancer activities, and their role in cardiovascular and neuroprotective prevention. This review aims to comprehensively analyze different studies performed on this class of compounds, their bioavailability and their therapeutic potential. An in-depth look in preclinical, in vitro and in vivo, and clinical studies indicates the preventive effects of anthocyanins on cardioprotection, neuroprotection, antiobesity as well as their antidiabetes and anticancer effects.

Berberis Plants-Drifting from Farm to Food Applications, Phytotherapy, and Phytopharmacology.

The genus Berberis includes about 500 different species and commonly grown in Europe, the United States, South Asia, and some northern areas of Iran and Pakistan. Leaves and fruits can be prepared as food flavorings, juices, and teas. Phytochemical analysis of these species has reported alkaloids, tannins, phenolic compounds and oleanolic acid, among others. Moreover, p-cymene, limonene and ocimene as major compounds in essential oils were found by gas chromatography. Berberis is an important group of the plants having enormous potential in the food and pharmaceutical industry, since they possess several properties, including antioxidant, antimicrobial, anticancer activities. Here we would like to review the biological properties of the phytoconstituents of this genus. We emphasize the cultivation control in order to obtain the main bioactive compounds, the antioxidant and antimicrobial properties in order to apply them for food preservation and for treating several diseases, such as cancer, diabetes or Alzheimer. However, further study is needed to confirm the biological efficacy as well as, the toxicity.

Dioscorea Plants: A Genus Rich in Vital Nutra-pharmaceuticals-A Review.

Dioscorea species, known as "Yams," belong to family Dioscoreaceae. This genus consists of more than 600 species distributed from Africa, Asia, the Caribbean's South America, and the South Pacific islands. Their organoleptic properties make them the most widely used carbohydrate food and dietary supplements. The underground and/or aerial tubers represent valuable sources of proteins, fats, and vitamins for millions of people in West Africa. This review gives a shot of secondary metabolites of Dioscorea plants, including steroids, clerodane diterpenes, quinones, cyanidins, phenolics, diarylheptanoids, and nitrogen-containing compounds. This review collected the evidence on biological properties of description Dioscorea, including in-vitro and in-vivo studies. Dioscorea species contain promising bioactive molecules i.e. diosgenin that support their different biological properties, including antioxidant, hypoglycaemic, hypolipidemic, anti- antimicrobial, inflammatory, antiproliferative, androgenic, estrogenic, and contraceptive drugs. Indeed, besides its nutrient values, Dioscorea is a potential source of bioactive substances of interest in the prevention/treatment of several diseases, and thus represents a great challenge in developing countries. However, ethnomedicinal potential should be validated and further researches on pharmacological properties and phytochemical composition should be carried out. Particularly, doing some studies to convert the preclinical results to clinical efficacy should be guaranteed. Dioscorea, Food plant, Traditional use, Phytochemistry, Pharmacological activities.

Resveratrol: A Double-Edged Sword in Health Benefits.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) belongs to polyphenols' stilbenoids group, possessing two phenol rings linked to each other by an ethylene bridge. This natural polyphenol has been detected in more than 70 plant species, especially in grapes' skin and seeds, and was found in discrete amounts in red wines and various human foods. It is a phytoalexin that acts against pathogens, including bacteria and fungi. As a natural food ingredient, numerous studies have demonstrated that resveratrol possesses a very high antioxidant potential. Resveratrol also exhibit antitumor activity, and is considered a potential candidate for prevention and treatment of several types of cancer. Indeed, resveratrol anticancer properties have been confirmed by many in vitro and in vivo studies, which shows that resveratrol is able to inhibit all carcinogenesis stages (e.g., initiation, promotion and progression). Even more, other bioactive effects, namely as anti-inflammatory, anticarcinogenic, cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective have also been reported. Nonetheless, resveratrol application is still being a major challenge for pharmaceutical industry, due to its poor solubility and bioavailability, as well as adverse effects. In this sense, this review summarized current data on resveratrol pharmacological effects.

Medicinal Plants Used in the Treatment of Human Immunodeficiency Virus.

Since the beginning of the epidemic, human immunodeficiency virus (HIV) has infected around 70 million people worldwide, most of whom reside is sub-Saharan Africa. There have been very promising developments in the treatment of HIV with anti-retroviral drug cocktails. However, drug resistance to anti-HIV drugs is emerging, and many people infected with HIV have adverse reactions or do not have ready access to currently available HIV chemotherapies. Thus, there is a need to discover new anti-HIV agents to supplement our current arsenal of anti-HIV drugs and to provide therapeutic options for populations with limited resources or access to currently efficacious chemotherapies. Plant-derived natural products continue to serve as a reservoir for the discovery of new medicines, including anti-HIV agents. This review presents a survey of plants that have shown anti-HIV activity, both in vitro and in vivo.

Phytotoxicity, Toxicity on Brine Shrimp and Insecticidal Effect of Chrysophthalmum gueneri Aytac & Anderb. Growing in Turkey.

OBJECTIVES: The aim of this study was to investigate the probable toxicity on brine shrimp, phytotoxicity, and insecticidal activity of Chrysophthalmum gueneri Aytac & Anderb. MATERIALS AND METHODS: The MeOH (80%) extract obtained from the whole plant of C. gueneri was fractionated through subsequent solvent extractions in increasing polarity with n-hexane, chloroform, and n-butanol. The MeOH (80%) extract and all fractions of C. gueneri were evaluated for their biologic activities using in vitro screening bioassays such as brine shrimp lethality test and phytotoxicity against Lemna minor, as well as insecticidal activity against Rhyzopertha dominica and Tribolium castaneum. RESULTS: The findings showed that the n-hexane and chloroform fractions of the plant had significant phytotoxic activities with 100% growth inhibition (GI) at 1000 µg/mL against L. minor. Moreover, the MeOH (80%) extract (53% GI) and n-butanol fraction (46.6% GI) of the plant had moderate phytotoxic activities at 1000 µg/mL. Otherwise, no samples had toxicity on the brine shrimps. In addition, the remaining water fraction had low insecticidal activity with 20% mortality against T. castaneum. CONCLUSION: Our results show that the n-hexane and chloroform fractions of C. gueneri had potential phytotoxic effects.

Cytotoxic, Phytotoxic and Insecticidal Activities of Chrysophthalmum montanum (DC.) Boiss.

OBJECTIVES: To investigate the in vitro cytotoxic, phytotoxic, and insecticidal activity of Chrysophthalmum montanum (DC.) Boiss. MATERIALS AND METHODS: The crude methanol (80%) extract of the aerial parts of C. montanum was fractionated to obtain n-hexane, chloroform, n-butanol, and remaining water fractions. The crude extract and subsequent solvent fractions of the plant were evaluated for their biological activities using screening bioassays such as cytotoxicity on brine shrimp lethality, phytotoxicity against Lemna minor L., and insecticidal activity against Rhyzopertha dominica and Tribolium castaneum. RESULTS: The cytotoxicity assay revealed that the crude extract, n-hexane, and chloroform fractions of the plant had positive lethality with LD50 values of 71.51, 126.62, and 75.95 µg/mL, respectively. The extract and its fractions, except for the remaining water fraction, showed phytotoxic activity, which was expressed as percentage growth regulation in a concentration-dependent manner. n-hexane and chloroform fractions in particular had 100% growth inhibition (GI) at 1000 µg/mL, followed by the n-butanol fraction (62.6% GI) and crude extract (40.0% GI) of the plant at the same concentration. Otherwise, all samples had no insecticidal activity against R. dominica and T. castaneum. CONCLUSION: This study demonstrates that C. montanum contains bioactive compounds related to potential biological activities such as cytotoxic and phytotoxic.

Exploring in vitro neurobiological effects and high-pressure liquid chromatography-assisted quantitation of chlorogenic acid in 18 Turkish coffee brands.

The hydroalcoholic extracts of the Turkish traditional coffee samples from 18 commercial brands were tested for their neurobiological effects through enzyme inhibition based on enzyme-linked immunosorbance microtiter assays against acetylcholinesterase, butyrylcholinesterase, and tyrosinase, linked to Alzheimer's and Parkinson's diseases. The extracts were also subjected to several antioxidant test systems to define their antiradical, metal-chelation capacity, and reducing power. Total phenol and flavonoid contents in the extracts were delineated by spectrophotometric methods, while chlorogenic acid in the coffee samples was quantified by high-pressure liquid chromatography. The extracts displayed low to moderate inhibition (from 2.13 ± 0.01% to 36.12 ± 1.07% at 200 µg/mL) against the tested enzymes, whereas they had notable 2,2'-diphenyl-1-picrylhydrazyl radical scavenging activity up to 56.15 ± 2.03% at 200 µg/mL. The extracts exerted a remarkable ferric-reducing antioxidant power values, while chlorogenic acid was found to range between 0.288 ± 0.005% and 2.335 ± 0.010%.

Antiprotozoal assessment and phenolic acid profiling of five Fumaria (fumitory) species.

OBJECTIVE: To explore some Fumaria species which were recorded to be traditionally used against malaria and other protozoal diseases. METHODS: Consequently, in the current study, antiprotozoal effect of the ethanol extracts obtained from five Fumaria species (Fumaria densiflora, Fumaria cilicica, Fumaria rostellata, Fumaria kralikii, and Fumaria parviflora) was investigated against the parasites; Plasmodium falciparum (malaria) and Trypanosoma bruceirhodesiense (human African trypanosomiasis) at 0.81 and 4.85 µg/mL concentrations. RESULTS: Among them, Fumaria densiflora extract exerted the highest antiplasmodial (93.80%) and antitrypanasomal effect (55.40%), while the ethanol extracts of Fumaria kralikii (43.45%) and Fumaria rostellata (41.65%) showed moderate activity against Plasmodium falciparum. Besides, phenolic acid contents of the extracts were analyzed using high performance liquid chromatography (HPLC) and trans-cinnamic (4.32 mg/g) and caffeic (3.71 mg/g) acids were found to be the dominant phenolic acids in Fumaria densiflora. CONCLUSIONS: According to our results, Fumaria densiflora deserve further study for its promising antiprotozoal activity.

Chemical and molecular aspects on interactions of galanthamine and its derivatives with cholinesterases.

Dual action of galanthamine as potent cholinesterase inhibitor and nicotinic modulator has attracted a great attention to be used in the treatment of AD. Consequently, galanthamine, a natural alkaloid isolated from a Galanthus species (snowdrop, Amaryllidaceae), has become an attractive model compound for synthesis of its novel derivatives to discover new drug candidates. Numerous studies have been done to elucidate interactions between galanthamine and its different derivatives and the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico experimental models. The in vitro studies revealed that galanthamine inhibits AChE in strong, competitive, long-acting, and reversible manner as well as BChE, although its selectivity towards AChE is much higher than BChE. The in silico studies carried out by employing molecular docking experiments as well as molecular dynamics simulations pointed out to existence of strong interactions of galanthamine with the active gorge of AChE, mostly of Torpedo californica (the Pasific electric ray) origin. In this review, we evaluate the mainstays of cholinesterase inhibitory action of galanthamine and its various derivatives from the point of view of chemical and molecular aspects.

Antiprotozoal assessment and phenolic acid profiling of five Fumaria (fumitory) species

Objective: To explore some Fumaria species which were recorded to be traditionally used against malaria and other protozoal diseases. Methods: Consequently, in the current study, antiprotozoal effect of the ethanol extracts obtained from five Fumaria species (Fumaria densiflora, Fumaria cilicica, Fumaria rostellata, Fumaria kralikii, and Fumaria parviflora) was investigated against the parasites; Plasmodium falciparum (malaria) and Trypanosoma bruceirhodesiense (human African trypanosomiasis) at 0.81 and 4.85 μg/mL concentrations. Results: Among them, Fumaria densiflora extract exerted the highest antiplasmodial (93.80%) and antitrypanasomal effect (55.40%), while the ethanol extracts of Fumaria kralikii (43.45%) and Fumaria rostellata (41.65%) showed moderate activity against Plasmodium falciparum. Besides, phenolic acid contents of the extracts were analyzed using high performance liquid chromatography (HPLC) and trans-cinnamic (4.32 mg/g) and caffeic (3.71 mg/g) acids were found to be the dominant phenolic acids in Fumaria densiflora. Conclusions: According to our results, Fumaria densiflora deserve further study for its promising antiprotozoal activity.

Urease inhibitory activity of ursane type sulfated saponins from the aerial parts of Zygophyllum fabago Linn.

Five ursane type sulfated saponins have been isolated from the aerial parts of Zygophyllum fabago Linn. (locally called Chashum). The urease inhibitory effects of these compounds have been investigated for the first time as well as their molecular docking studies have also been carried out to check the structure-activity relationship. The IC50 values of these compounds could not be found due to paucity of the samples. The molecular docking studies were performed only for the most active compound mono sodium salt of 3ß,23-di-O-sulfonyl-23-hydroxyurs-20(21)-en-28-oic acid 28-O-[ß-D-glucopyranosyl] ester (Zygofaboside A; 1).

Anti-hepatitis B activity of isoquinoline alkaloids of plant origin.

Hepatitis B virus (HBV) is the causative agent of B-type hepatitis in humans, a vaccine-preventable disease. Despite the availability of effective vaccines, globally, 2 billion people show evidence of past or current HBV infection, of which 350 million people are persistently infected, with an estimated annual increase of 1 million. There is no cure for chronic HBV infections, which are associated with cirrhotic liver failure and with an increased risk of developing hepatocellular carcinoma. Hepatitis antiviral research has focused primarily on the development of inhibitors of viral polymerase through the use of nucleoside analogues. Therefore, there is an urgent need for the development of non-nucleoside compounds to be used as an alternative or to complement the current therapy. To address this need, 18 isoquinoline alkaloids were evaluated for their potential antiviral activity against HBV in vitro.

Studies on α-glucosidase inhibition and anti-glycation potential of Iris loczyi and Iris unguicularis.

AIMS: One of the aims of this research work is the isolation and identification of various constituents of two medicinally important plants (Iris loczyi and Iris unguicularis). Secondly, the prime aim is the biological evaluation of these natural products to discover new potential inhibitors of α-glucosidase enzyme and protein glycation. MAIN METHODS: Plants of the genus Iris contain a variety of secondary metabolites. Chromatographic techniques were applied for the isolation of different compounds from Iris loczyi and Iris unguicularis. All the isolated compounds were screened for their α-glucosidase enzyme inhibition and antiglycation potential. KEY FINDINGS: It is shown in the results that two compounds (Kaempferol and 8-Methoxyeriodictyol) isolated from plant Iris unguicularis and compounds (Arborinone and 5,7-dihydroxy-2',6-dimethoxyisoflavone) isolated from plant Iris loczyi possess promising activity against α-glucosidase enzyme as compare to acarbose which is used as a standard α-glucosidase inhibitor in this study. A flavanone (2',5-dihydroxy-6,7-methylenedioxy) isolated from Iris loczyi was explored as most active anti-glycating agent. SIGNIFICANCE: α-Glucosidase enzyme is a therapeutic target to treat carbohydrate mediated diseases. In this study various inhibitors of α-glucosidase are identified which might be important for the management of diabetes. Similarly, antiglycation agents may have application for the management of late diabetic complications.

Antioxidant and hepatoprotective activity appraisal of four selected Fumaria species and their total phenol and flavonoid quantities.

Fumaria species (Fumariaceae) have been recorded to be used traditionally against liver-related disorders in many countries including Turkey. Oxidative stress is also known to be strongly associated with hepatic problems. Consequently, in the current study, the ethanol extracts of four Fumaria species; F. cilicica Hausskn., F. densiflora DC., F. kralikii Jordan and F. parviflora Lam. growing in Turkey were initially screened for their in vitro antioxidant activities by three methods; 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging test, Fe(+2)-ferrozine test system for metal chelating test and ferric-ion reducing antioxidant power (FRAP) at 250, 500 and 1000 µg/ml concentrations. Then, each of the ethanol extracts was fractionated into petroleum ether, chloroform, ethyl acetate and methanol fractions and their antioxidant activities were estimated by DPPH radical scavenging and xanthine oxidase inhibition tests at 1000 µg/ml. In both tests, the chloroform and ethyl acetate fractions of F. cilicica were found to be the most active and were further investigated in in vivo hepatoprotective activity experiment against toxicity induced by CCl(4). Total phenol and flavonoid quantities of the ethanol extracts were determined spectrophotometrically using Folin-Ciocalteau's and AlCl(3) reagents, respectively. Our data revealed that the chloroform and ethyl acetate fractions of F. cilicica did not have hepatoprotective effect and the ethanol extracts exerted low antioxidant activity. Although protective effect of some Fumaria species in hepatic diseases was shown in several previous studies, this record seems to be not pertinent for F. cilicica.