scholarly journals Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zinuo Chen ◽  
Qinghua Cui ◽  
Laura Cooper ◽  
Pin Zhang ◽  
Hyun Lee ◽  
...  
Keyword(s):  
Natural Products ◽  
Mechanism Of Action ◽  
Cysteine Proteases ◽  
Anacardic Acid ◽  
Lead Compounds ◽  
Irreversible Inhibitors ◽  
Ginkgolic Acid ◽  
Covalent Inhibitors ◽  
Dual Inhibitors

Abstract Background In the urgent campaign to develop therapeutics against SARS-CoV-2, natural products have been an important source of new lead compounds. Results We herein identified two natural products, ginkgolic acid and anacardic acid, as inhibitors using a high-throughput screen targeting the SARS-CoV-2 papain-like protease (PLpro). Moreover, our study demonstrated that the two hit compounds are dual inhibitors targeting the SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) in addition to PLpro. A mechanism of action study using enzyme kinetics further characterized the two compounds as irreversible inhibitors against both 3CLpro and PLpro. Significantly, both identified compounds inhibit SARS-CoV-2 replication in vitro at nontoxic concentrations. Conclusions Our finding provides two novel natural products as promising SARS-CoV-2 antivirals.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

2018 ◽  
Author(s):  
Jonathan J. Mills ◽  
Kaylib R. Robinson ◽  
Troy E. Zehnder ◽  
Joshua G. Pierce
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Mechanism Of Action ◽  
Marine Natural Products ◽  
Biological Evaluation ◽  
Lead Compounds ◽  
Follow Up Studies ◽  
Initial Resistance ◽  
Synthesis And Biological Evaluation

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

scholarly journals In Vitro Evaluation of Neutral Aryloximes as Reactivators for Electrophorus eel Acetylcholinesterase Inhibited by Paraoxon

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 583 ◽  
Author(s):  
Daniel Kitagawa ◽  
Samir Cavalcante ◽  
Reuel de Paula ◽  
Rafael Rodrigues ◽  
Leandro Bernardo ◽  
...  
Keyword(s):  
Organophosphorus Pesticides ◽  
Structural Factors ◽  
Poor Countries ◽  
Lead Compounds ◽  
Irreversible Inhibitors ◽  
Sar Studies ◽  
Pyridinium Oximes ◽  
The Central Nervous System ◽  
Enzyme Reactivation

Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.

scholarly journals Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

2016 ◽  
Vol 60 (6) ◽  
pp. 3802-3812 ◽  
Author(s):  
Ylenia Baquedano ◽  
Verónica Alcolea ◽  
Miguel Ángel Toro ◽  
Killian Jesús Gutiérrez ◽  
Paul Nguewa ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Inhibitory Activity ◽  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Content Type ◽  
Bioactive Scaffolds ◽  
Lead Compounds ◽  
Novel Structures ◽  
Micromolar Range

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and theirin vitroleishmanicidal activities againstLeishmania infantumamastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 μM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3′-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

scholarly journals The Medicinal Timber Canarium patentinervium Miq. (Burseraceae Kunth.) Is an Anti-Inflammatory Bioresource of Dual Inhibitors of Cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX)

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
R. Mogana ◽  
K. Teng-Jin ◽  
C. Wiart
Keyword(s):  
Inflammatory Diseases ◽  
Ethanolic Extract ◽  
Ethanol Extract ◽  
Frap Assay ◽  
Dual Inhibitor ◽  
Lead Compounds ◽  
Dual Inhibitors ◽  
Cox 2 ◽  
Cox 1

The barks and leaves extracts of Canarium patentinervium Miq. (Burseraceae Kunth.) were investigated for cyclooxygenase (COX) and 5-lipoxygenase (LOX) inhibition via in vitro models. The corresponding antioxidative power of the plant extract was also tested via nonenzyme and enzyme in vitro assays. The ethanolic extract of leaves inhibited the enzymatic activity of 5-LOX, COX-1, and COX-2 with IC50 equal to 49.66±0.02 μg/mL, 0.60±0.01 μg/mL, and 1.07±0.01 μg/mL, respectively, with selective COX-2 activity noted in ethanolic extract of barks with COX-1/COX-2 ratio of 1.22. The ethanol extract of barks confronted oxidation in the ABTS, DPPH, and FRAP assay with EC50 values equal to 0.93±0.01 μg/mL, 2.33±0.02 μg/mL, and 67.00±0.32 μg/mL, respectively, while the ethanol extract of leaves confronted oxidation in β-carotene bleaching assay and superoxide dismutase (SOD) assay with EC50 value of 6.04±0.02 μg/mL and IC50 value of 3.05±0.01 μg/mL. The ethanol extract acts as a dual inhibitor of LOX and COX enzymes with potent antioxidant capacity. The clinical significance of these data is quite clear that they support a role for Canarium patentinervium Miq. (Burseraceae Kunth.) as a source of lead compounds in the management of inflammatory diseases.

scholarly journals In Vitro Anti-proliferative Effect of Naturally Occurring Oxyprenylated Chalcones

2013 ◽  
Vol 8 (8) ◽  
pp. 1934578X1300800 ◽  
Author(s):  
Serena Fiorito ◽  
Francesco Epifano ◽  
Celine Bruyère ◽  
Robert Kiss ◽  
Salvatore Genovese
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Colorimetric Assay ◽  
Appreciable Effect ◽  
Proliferative Effect ◽  
Mtt Colorimetric Assay ◽  
Naturally Occurring

As a continuation of our ongoing studies aimed to depict the effects and mechanism of action of naturally occurring oxyprenylated phenylpropanoids and polyketides, in this paper we describe the synthesis and in vitro anti-proliferative effects of selected compounds belonging to the above cited classes of secondary metabolites on six cancer cell lines using the MTT colorimetric assay. Our study revealed that among the natural products tested, only oxyprenylated chalcones exhibited an appreciable effect (mean IC50 = 32 - 64 μM), while substituted alcohols, phenylpropenes, naphthoquinones, and aminoacid derivatives were by far less active or inactive.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

2018 ◽  
Author(s):  
Jonathan J. Mills ◽  
Kaylib R. Robinson ◽  
Troy E. Zehnder ◽  
Joshua G. Pierce
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Mechanism Of Action ◽  
Marine Natural Products ◽  
Biological Evaluation ◽  
Lead Compounds ◽  
Follow Up Studies ◽  
Initial Resistance ◽  
Synthesis And Biological Evaluation

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

In silico identification and in vitro activity of natural products as ADP-ribosyl transferase member 8 inhibitors

2020 ◽  
Vol 12 (19) ◽  
pp. 1729-1741
Author(s):  
Stephanie S Schweiker ◽  
Amanda L Tauber ◽  
Stephan M Levonis
Keyword(s):  
Natural Products ◽  
Catalytic Domain ◽  
Epigallocatechin Gallate ◽  
In Vitro Activity ◽  
Autodock Vina ◽  
Conserved Residues ◽  
Lead Compounds ◽  
Anti Cancer ◽  
In Silico Identification

Aim: ADP-ribosyl transferase member 8 (ARTD8) of the ARTD superfamily has been identified as a possible anti-cancer, antiviral and anti-inflammatory target. Method: Pure actives from natural products with a documented anti-cancer activity were docked into the catalytic site of 3SMI.pdb using PyRx and AutoDock Vina. Results: Epigallocatechin gallate (EGCG), trans-resveratrol, indol-3-carbinol, curcumin, quercetin and naringenin were investigated, in vitro, against ARTD8, revealing EGCG and quercetin as lead compounds, with EGCG displaying complete inhibition at 10 μM. Both EGCG and quercetins docked poses spanned across both the nicotinamide and adenine subsites of the catalytic domain, interacting with conserved residues Ser1641 and/or Ser1607 and Tyr1646. Thereby, suggesting that the meta-hydroxy group on the catechin ring B backbone may be responsible for these inhibition effects.

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

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6004
Author(s):  
Anusree Venkidath ◽  
Jong Min Oh ◽  
Sanal Dev ◽  
Elham Amin ◽  
Shebina P. Rasheed ◽  
...  
Keyword(s):  
Mao B ◽  
Lead Compounds ◽  
Small Series ◽  
Ic50 Value ◽  
Competitive Inhibitors ◽  
Docking Approach ◽  
Ic50 Values ◽  
Dual Inhibitors ◽  
Better Than

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 Ki 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.

Investigation of in vitro antifungal efficacy of selected extracts of Greek natural products on Malassezia sps

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
A Velegraki ◽  
K Graikou ◽  
S Kritikou ◽  
M Varsani ◽  
I Chinou
Keyword(s):  
Natural Products ◽  
Antifungal Efficacy

The Effect of Dipyridamole and RA 233 on Human Platelet Function in Vitro

1973 ◽  
Vol 29 (03) ◽  
pp. 694-700 ◽  
Author(s):  
Paul L. Rifkin ◽  
Marjorie B. Zucker
Keyword(s):  
Mechanism Of Action ◽  
Human Blood ◽  
Glass Bead ◽  
Heart Valves ◽  
Human Platelet ◽  
Drug Effects ◽  
Simple Relation ◽  
Prosthetic Heart Valves ◽  
Induced Aggregation

SummaryDipyridamole (Persantin) is reported to prolong platelet survival and inhibit embolism in patients with prosthetic heart valves, but its mechanism of action is unknown. Fifty jxM dipyridamole failed to reduce the high percentage of platelets retained when heparinized human blood was passed through a glass bead column, but prolonged the inhibition of retention caused by disturbing blood in vitro. Possibly the prostheses act like disturbance. Although RA 233 was as effective as dipyridamole in inhibiting the return of retention, it was less effective in preventing the uptake of adenosine into erythrocytes, and more active in inhibiting ADP-induced aggregation and release. Thus there is no simple relation between these drug effects.

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