Medicarpin and Homopterocarpin Isolated from Canavalia lineata as Potent and Competitive Reversible Inhibitors of Human Monoamine Oxidase-B

Thirteen compounds were isolated from the Canavalia lineata pods and their inhibitory activities against human monoamine oxidase-A (hMAO-A) and -B (hMAO-B) were evaluated. Among them, compounds 8 (medicarpin) and 13 (homopterocarpin) showed potent inhibitory activity against hMAO-B (IC₅₀ = 0.45 and 0.72 µM, respectively) with selectivity index (SI) values of 44.2 and 2.07, respectively. Most of the compounds weakly inhibited MAO-A, except 9 (prunetin) and 13. Compounds 8 and 13 were reversible competitive inhibitors against hMAO-B (K_i = 0.27 and 0.21 µM, respectively). Structurally, the 3-OH group at A-ring of 8 showed higher hMAO-B inhibitory activity than 3-OCH3 group at the A-ring of 13. However, the 9-OCH3 group at B-ring of 13 showed higher hMAO-B inhibitory activity than 8,9-methylenedioxygroup at the B-ring of 12 (pterocarpin). In cytotoxicity study, 8 and 13 showed non-toxicity to the normal (MDCK) and cancer (HL-60) cells and moderate toxicity to neuroblastoma (SH-SY5Y) cell. Molecular docking simulation revealed that the binding affinities of 8 and 13 for hMAO-B (−8.7 and −7.7 kcal/mol, respectively) were higher than those for hMAO-A (−3.4 and −7.1 kcal/mol, respectively). These findings suggest that compounds 8 and 13 be considered potent reversible hMAO-B inhibitors to be used for the treatment of neurological disorders.     

Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate

Widespread pathologies such as atherosclerosis, metabolic syndrome and cancer are associated with dysregulation of sterol biosynthesis and metabolism. Cholesterol modulates the signaling pathways of neoplastic transformation and tumor progression. Lanosterol 14-alpha demethylase (cytochrome P450(51), CYP51A1) catalyzes one of the key steps in cholesterol biosynthesis. The fairly low somatic mutation frequency of CYP51A1, its druggability, as well as the possibility of interfering with cholesterol metabolism in cancer cells collectively suggest the clinical importance of CYP51A1. Here, we show that the natural flavonoid, luteolin 7,3′-disulfate, inhibits CYP51A1 activity. We also screened baicalein and luteolin, known to have antitumor activities and low toxicity, for their ability to interact with CYP51A1. The K_d values were estimated using both a surface plasmon resonance optical biosensor and spectral titration assays. Unexpectedly, in the enzymatic activity assays, only the water-soluble form of luteolin—luteolin 7,3′-disulfate—showed the ability to potently inhibit CYP51A1. Based on molecular docking, luteolin 7,3′-disulfate binding suggests blocking of the substrate access channel. However, an alternative site on the proximal surface where the redox partner binds cannot be excluded. Overall, flavonoids have the potential to inhibit the activity of human CYP51A1 and should be further explored for their cholesterol-lowering and anti-cancer activity.     

Design,Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors

Twelve pyridazinones (T1–T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC₅₀ value of 0.013 µM, followed by T3 (IC₅₀ = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH₃)₂ (T12) > -OCH₃ (T9) > Br (T7) > F (T5) > -CH₃ (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC₅₀ values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with K_i values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer’s disease.     

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection,Neurological Disorders,and Neuroblastoma

Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that patients with atypical depression preferentially respond to natural product MAOIs. This review presents a comprehensive survey of the natural products, predominantly from plant sources, as potential new MAOI drug leads. The psychoactive properties of several traditionally used plants and herbal formulations were attributed to their MAOI constituents. MAO inhibitory constituents may also be responsible for neuroprotective effects of natural products. Different classes of MAOIs were identified from the natural product sources with non-selective as well as selective inhibition of MAO-A and -B. Selective reversible natural product MAOIs may be safer alternatives to the conventional MAOI drugs. Characterization of MAO inhibitory constituents of natural products traditionally used as psychoactive preparations or for treatment of neurological disorders may help in understanding the mechanism of action, optimization of these preparations for desired bioactive properties, and improvement of the therapeutic potential. Potential therapeutic application of natural product MAOIs for treatment of neuroblastoma is also discussed.     

Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors

A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC₅₀ value = 0.0092 and 0.016 µM, respectively) than the standards (IC₅₀ value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with K_i values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC₅₀ values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.     

Flavonoid Constituents and Alpha-Glucosidase Inhibition of Solanum stramonifolium Jacq. Inflorescence with In Vitro and In Silico Studies

Solanum stramonifolium Jacq. (Solanaceae) is widely found in South East Asia. In Thailand, it is used as vegetable and as a component in traditional recipes. The results of an alpha-glucosidase inhibitory screening test found that the crude extract of S. stramonifolium inflorescence exhibited the potential effect with IC₅₀ 81.27 μg/mL. The separation was performed by the increasing solvent polarity method. The ethyl acetate, ethanol, and water extracts of S. stramonifolium inflorescence showed the synergistic effect together with acarbose standard. The phytochemical investigation of these extracts was conducted by chromatographic and spectroscopic techniques. Six flavonoid compounds, myricetin 3, 4′, 5′, 7-tetramethyl ether (1), combretol (2), kaempferol (3), kaempferol 7-O-glucopyranoside (4), 5-hydroxy 3-7-4′-5′-tetramethoxyflavone-3′-O-glucopyranoside (5), and a mixture (6) of isorhamnetin 3-O-glucopyranoside (6a) and astragalin (6b) were isolated. This discovery is the first report of flavonoid-glycoside 5. Moreover, the selected flavonoids, kaempferol and astragalin, were representatives to explore the mechanism of action. Both of them performed mixed-type inhibition. The molecular docking gave a better understanding of flavonoid compounds’ ability to inhibit the alpha-glucosidase enzyme.     

Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases

Inhibition of bacterial virulence is believed to be a new treatment option for bacterial infections. In the present study, we tested dipicolylamine (DPA), tripicolylamine (TPA), tris pyridine ethylene diamine (TPED), pyridine and thiophene derivatives as putative inhibitors of the bacterial virulence factors thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) and the human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14). These compounds have nitrogen or sulfur as putative donor atoms for zinc chelation. In general, the compounds showed stronger inhibition of MMP-14 and PLN than of the other enzymes, with K_i values in the lower μM range. Except for DPA, none of the compounds showed significantly stronger inhibition of the virulence factors than of the human zinc metalloproteases. TPA and Zn230 were the only compounds that inhibited all five zinc metalloproteinases with a K_i value in the lower μM range. The thiophene compounds gave weak or no inhibition. Docking indicated that some of the compounds coordinated zinc by one oxygen atom from a hydroxyl or carbonyl group, or by oxygen atoms both from a hydroxyl group and a carbonyl group, and not by pyridine nitrogen as in DPA and TPA.     

Molecular Modeling and Experimental Evaluation of Non-Chiral Components of Bergamot Essential Oil with Inhibitory Activity against Human Monoamine Oxidases

Human monoamine oxidases (hMAOs) are well-established targets for the treatment of neurological disorders such as depression, Parkinson’s disease and Alzheimer’s disease. Despite the efforts carried out over the years, few selective and reversible MAO inhibitors are on the market. Thus, a continuous search for new compounds is needed. Herein, MAO inhibitors were searched among the non-chiral constituents of Bergamot Essential Oil (BEO) with the aid of computational tools. Accordingly, molecular modeling simulations were carried out on both hMAO-A and hMAO-B for the selected constituents. The theoretically predicted target recognition was then used to select the most promising compounds. Among the screened compounds, Bergamottin, a furocoumarin, showed selective hMAO-B inhibitory activity, fitting its active site well. Molecular dynamics simulations were used to deeply analyze the target recognition and to rationalize the selectivity preference. In agreement with the computational results, experimental studies confirmed both the hMAO inhibition properties of Bergamottin and its preference for the isoform B.     

Phytochemical Profiling,In Vitro Biological Activities,and In Silico Molecular Docking Studies of Dracaena reflexa

Dracaena reflexa, a traditionally significant medicinal plant, has not been extensively explored before for its phytochemical and biological potential. The present study was conducted to evaluate the bioactive phytochemicals and in vitro biological activities of D. reflexa, and perform in silico molecular docking validation of D. reflexa. The bioactive phytochemicals were assessed by preliminary phytochemical testing, total bioactive contents, and GC-MS analysis. For biological evaluation, the antioxidant (DPPH, ABTS, CUPRAC, and ABTS), antibacterial, thrombolytic, and enzyme inhibition (tyrosinase and cholinesterase enzymes) potential were determined. The highest level of total phenolic contents (92.72 ± 0.79 mg GAE/g extract) was found in the n-butanol fraction while the maximum total flavonoid content (110 ± 0.83 mg QE/g extract) was observed in methanolic extract. The results showed that n-butanol fraction exhibited very significant tyrosinase inhibition activity (73.46 ± 0.80) and acetylcholinesterase inhibition activity (64.06 ± 2.65%) as compared to other fractions and comparable to the standard compounds (kojic acid and galantamine). The methanolic extract was considered to have moderate butyrylcholinesterase inhibition activity (50.97 ± 063) as compared to the standard compound galantamine (53.671 ± 0.97%). The GC-MS analysis of the n-hexane fraction resulted in the tentative identification of 120 bioactive phytochemicals. Furthermore, the major compounds as identified by GC-MS were analyzed using in silico molecular docking studies to determine the binding affinity between the ligands and the enzymes (tyrosinase, acetylcholinesterase, and butyrylcholinesterase enzymes). The results of this study suggest that Dracaena reflexa has unquestionable pharmaceutical importance and it should be further explored for the isolation of secondary metabolites that can be employed for the treatment of different diseases.     

7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries Are Potent and Selective Inhibitors of DNA Methyltransferase 1

Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. To advance epigenetic probes and drug discovery, chemical companies are developing focused libraries for epigenetic targets. Based on a knowledge-based approach, herein we report the identification of two quinazoline-based derivatives identified in focused libraries with sub-micromolar inhibition of DNMT1 (30 and 81 nM), more potent than S-adenosylhomocysteine. Also, both compounds had a low micromolar affinity of DNMT3A and did not inhibit DNMT3B. The enzymatic inhibitory activity of DNMT1 and DNMT3A was rationalized with molecular modeling. The quinazolines reported in this work are known to have low cell toxicity and be potent inhibitors of the epigenetic target G9a. Therefore, the quinazoline-based compounds presented are attractive not only as novel potent inhibitors of DNMTs but also as dual and selective epigenetic agents targeting two families of epigenetic writers.     

Inhibition of Aldose Reductase by Ginsenoside Derivatives via a Specific Structure Activity Relationship with Kinetics Mechanism and Molecular Docking Study

This present work is designed to evaluate the anti-diabetic potential of 22 ginsenosides via the inhibition against rat lens aldose reductase (RLAR), and human recombinant aldose reductase (HRAR), using _DL-glyceraldehyde as a substrate. Among the ginsenosides tested, ginsenoside Rh2, (20S) ginsenoside Rg3, (20R) ginsenoside Rg3, and ginsenoside Rh1 inhibited RLAR significantly, with IC₅₀ values of 0.67, 1.25, 4.28, and 7.28 µM, respectively. Moreover, protopanaxadiol, protopanaxatriol, compound K, and ginsenoside Rh1 were potent inhibitors of HRAR, with IC₅₀ values of 0.36, 1.43, 2.23, and 4.66 µM, respectively. The relationship of structure–activity exposed that the existence of hydroxyl groups, linkages, and their stereo-structure, as well as the sugar moieties of the ginsenoside skeleton, represented a significant role in the inhibition of HRAR and RLAR. Additional, various modes of ginsenoside inhibition and molecular docking simulation indicated negative binding energies. It was also indicated that it has a strong capacity and high affinity to bind the active sites of enzymes. Further, active ginsenosides suppressed sorbitol accumulation in rat lenses under high-glucose conditions, demonstrating their potential to prevent sorbitol accumulation ex vivo. The findings of the present study suggest the potential of ginsenoside derivatives for use in the development of therapeutic or preventive agents for diabetic complications.     

Synthesis,Structure and Impact of 5-Aminoorotic Acid and Its Complexes with Lanthanum(III) and Gallium(III) on the Activity of Xanthine Oxidase

The superoxide radical ion is involved in numerous physiological processes, associated with both health and pathology. Its participation in cancer onset and progression is well documented. Lanthanum(III) and gallium(III) are cations that are known to possess anticancer properties. Their coordination complexes are being investigated by the scientific community in the search for novel oncological disease remedies. Their complexes with 5-aminoorotic acid suppress superoxide, derived enzymatically from xanthine/xanthine oxidase (X/XO). It seems that they, to differing extents, impact the enzyme, or the substrate, or both. The present study closely examines their chemical structure by way of modern methods—IR, Raman, and ¹H NMR spectroscopy. Their superoxide-scavenging behavior in the presence of a non-enzymatic source (potassium superoxide) is compared to that in the presence of an enzymatic source (X/XO). Enzymatic activity of XO, defined in terms of the production of uric acid, seems to be impacted by both complexes and the pure ligand in a concentration-dependent manner. In order to better relate the compounds’ chemical characteristics to XO inhibition, they were docked in silico to XO. A molecular docking assay provided further proof that 5-aminoorotic acid and its complexes with lanthanum(III) and gallium(III) very probably suppress superoxide production via XO inhibition.     

In Silico Screening and In Vitro Assessment of Natural Products with Anti-Virulence Activity against Helicobacter pylori

Helicobacter pylori is one of the most frequent human pathogens and a leading etiological agent of various gastric diseases. As stringent response, coordinated by a SpoT protein, seems to be crucial for the survivability of H. pylori, the main goal of this article was to use in silico computational studies to find phytochemical compounds capable of binding to the active site of SpoT from H. pylori and confirm the ability of the most active candidates to interfere with the virulence of this bacterium through in vitro experiments. From 791 natural substances submitted for the virtual screening procedure, 10 were chosen and followed for further in vitro examinations. Among these, dioscin showed the most interesting parameters (the lowest MIC, the highest anti-biofilm activity in static conditions, and a relatively low stimulation of morphological transition into coccoids). Therefore, in the last part, we extended the research with a number of further experiments and observed the ability of dioscin to significantly reduce the formation of H. pylori biofilm under Bioflux-generated flow conditions and its capacity for additive enhancement of the antibacterial activity of all three commonly used antibiotics (clarithromycin, metronidazole, and levofloxacin). Based on these results, we suggest that dioscin may be an interesting candidate for new therapies targeting H. pylori survivability and virulence.     

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.     

Synthesis,characterization and biological activities of two novel orthopalladated complexes: Interactions with DNA and bovine serum albumin,antitumour activity and molecular docking studies

[Pd(L₁)(C,N)]CF₃SO₃ and [Pd(L₂)(C,N)]CF₃SO₃ (L₁ = 2,2′ ‐bipyridine, L₂ = 1,10‐phenanthroline and C,N = benzylamine) novel orthopalladated complexes have been synthesized and characterized using various techniques. The binding of the complexes with native calf thymus DNA (CT‐DNA) was monitored using UV–visible absorption spectrophotometry, fluorescence spectroscopy and thermal denaturation studies. Our results indicate that these complexes can strongly bind to CT‐DNA via partial intercalative mode. In addition, fluorescence spectrometry of bovine serum albumin (BSA) with the complexes shows that the fluorescence quenching mechanism of BSA is a static process. The results of site‐competitive replacement experiments with specific site markers clearly indicate that the complexes bind to site I of BSA. Notably, the complexes exhibit significant in vitro cytotoxicity against two human cancer cell lines (Jurkat and MCF‐7) with IC₅₀ values varying from 37 to 53 μM. Finally, a molecular docking experiment effectively proves the binding of the Pd(II) complexes to DNA and BSA.     

Chemical Composition and Antioxidant,Anti-Inflammatory,and Enzyme Inhibitory Activities of an Endemic Species from Southern Algeria: Warionia saharae

Warionia saharae Benth. & Coss. (Asteraceae) is an endemic species of North Africa naturally grown in the southwest of the Algerian Sahara. In the present study, this species’ hydromethanolic leaf extract was investigated for its phenolic profile characterized by ultra-high-performance liquid chromatography coupled with a diode array detector and an electrospray mass spectrometer (UHPLC-DAD-ESI/MS). Additionally, the chemical composition of W. saharae was analyzed by gas chromatography–mass spectrometry, and its antioxidant potential was assessed through five in vitro tests: DPPH^● scavenging activity, ABTS^●+ scavenging assay, galvinoxyl scavenging activity, ferric reducing power (FRP), and cupric reducing antioxidant capacity. The UHPLC-DAD-ESI/MS analysis allowed the detection and quantification of 22 compounds, with taxifolin as the dominant compound. The GC–MS analysis allowed the identification of 37 compounds, and the antioxidant activity data indicate that W. saharae extract has a very high capacity to capture radicals due to its richness in compounds with antioxidant capacity. The extract also showed potent α-glucosidase inhibition as well as a good anti-inflammatory activity. However, weak anti-α-amylase and anticholinesterase activities were recorded. Moreover, an in silico docking study was performed to highlight possible interactions between three significant compounds identified in W. saharae extract and α-glucosidase enzyme.     

Advances in Fungal Phenaloenones—Natural Metabolites with Great Promise: Biosynthesis,Bioactivities, and an In Silico Evaluation of Their Potential as Human Glucose Transporter 1 Inhibitors

Phenaloenones are structurally unique aromatic polyketides that have been reported in both microbial and plant sources. They possess a hydroxy perinaphthenone three-fused-ring system and exhibit diverse bioactivities, such as cytotoxic, antimicrobial, antioxidant, and anti-HIV properties, and tyrosinase, α-glucosidase, lipase, AchE (acetylcholinesterase), indoleamine 2,3-dioxygenase 1, angiotensin-I-converting enzyme, and tyrosine phosphatase inhibition. Moreover, they have a rich nucleophilic nucleus that has inspired many chemists and biologists to synthesize more of these related derivatives. The current review provides an overview of the reported phenalenones with a fungal origin, including their structures, sources, biosynthesis, and bioactivities. Moreover, more than 135 metabolites have been listed, and 71 references have been cited. SuperPred, an artificial intelligence (AI) webserver, was used to predict the potential targets for selected phenalenones. Among these targets, we chose human glucose transporter 1 (hGLUT1) for an extensive in silico study, as it shows high probability and model accuracy. Among them, aspergillussanones C (60) and G (60) possessed the highest negative docking scores of −15.082 and −14.829 kcal/mol, respectively, compared to the native inhibitor of 5RE (score: −11.206 kcal/mol). The MD (molecular dynamics) simulation revealed their stability in complexes with GLUT1 at 100 ns. The virtual screening study results open up a new therapeutic approach by using some phenalenones as hGLUT1 inhibitors, which might be a potential target for cancer therapy.