Exploring Amantadine Derivatives as Urease Inhibitors: Molecular Docking and Structure–Activity Relationship (SAR) Studies

This article describes the design and synthesis of a series of novel amantadine-thiourea conjugates (3a–j) as Jack bean urease inhibitors. The synthesized hybrids were assayed for their in vitro urease inhibition. Accordingly, N-(adamantan-1-ylcarbamothioyl)octanamide (3j) possessing a 7-carbon alkyl chain showed excellent activity with IC50 value 0.0085 ± 0.0011 µM indicating that the long alkyl chain plays a vital role in enzyme inhibition. Whilst N-(adamantan-1-ylcarbamothioyl)-2-chlorobenzamide (3g) possessing a 2-chlorophenyl substitution was the next most efficient compound belonging to the aryl series with IC50 value of 0.0087 ± 0.001 µM. The kinetic mechanism analyzed by Lineweaver–Burk plots revealed the non-competitive mode of inhibition for compound 3j. Moreover, in silico molecular docking against target protein (PDBID 4H9M) indicated that most of the synthesized compounds exhibit good binding affinity with protein. The compound 3j forms two hydrogen bonds with amino acid residue VAL391 having a binding distance of 1.858 Å and 2.240 Å. The interaction of 3j with amino acid residue located outside the catalytic site showed its non-competitive mode of inhibition. Based upon these results, it is anticipated that compound 3j may serve as a lead structure for the design of more potent urease inhibitors.

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Hybrid Pharmacophoric Approach in the Design and Synthesis of Coumarin Linked Pyrazolinyl as Urease Inhibitors, Kinetic Mechanism and Molecular Docking

Chemistry & Biodiversity ◽

10.1002/cbdv.201700035 ◽

2017 ◽

Vol 14 (8) ◽

pp. e1700035 ◽

Cited By ~ 19

Author(s):

Aamer Saeed ◽

Parvez Ali Mahesar ◽

Pervaiz Ali Channar ◽

Fayaz Ali Larik ◽

Qamar Abbas ◽

...

Keyword(s):

Molecular Docking ◽

Kinetic Mechanism ◽

Urease Inhibitors ◽

Design And Synthesis

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In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

Molecules ◽

10.3390/molecules26144147 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4147

Author(s):

Neha Gupta ◽

Saurav Kumar Choudhary ◽

Neeta Bhagat ◽

Muthusamy Karthikeyan ◽

Archana Chaturvedi

Keyword(s):

Molecular Docking ◽

Amino Acid ◽

Guanylyl Cyclase ◽

Extracellular Domain ◽

Enterotoxigenic Escherichia Coli ◽

Watery Diarrhea ◽

Guanylyl Cyclase C ◽

Amino Acid Residues ◽

Lead Compounds

The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein–protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.

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Synthesis, biological assay in vitro and molecular docking studies of new Schiff base derivatives as potential urease inhibitors

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2011.09.009 ◽

2011 ◽

Vol 46 (11) ◽

pp. 5473-5479 ◽

Cited By ~ 101

Author(s):

Muhammad Adil S. Aslam ◽

Shams-ul Mahmood ◽

Mohammad Shahid ◽

Aamer Saeed ◽

Jamshed Iqbal

Keyword(s):

Schiff Base ◽

Molecular Docking ◽

Docking Studies ◽

Biological Assay ◽

Urease Inhibitors ◽

Molecular Docking Studies ◽

Schiff Base Derivatives

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Synthesis and Molecular Drug Validations of 1H-Benzo[d]imidazol-2-amine Derivatives: Molecular Docking and its Biological Activities

Asian Journal of Chemistry ◽

10.14233/ajchem.2019.22104 ◽

2019 ◽

Vol 31 (9) ◽

pp. 2057-2064

Author(s):

S.R. Ashok ◽

M.K. Shivananda ◽

A. Manikandan

Keyword(s):

Molecular Docking ◽

Biological Activities ◽

Radical Scavenging ◽

Vital Role ◽

Cancer Development ◽

Anticancer Properties ◽

Drug Designing ◽

Prostaglandin Endoperoxide Synthase ◽

Cancer Types

Molecular adaptation of small molecules that are targeted as therapeutic agents is a most anticipated one in drug designing and development. In the present approach, a family of substituted 1H-benzo[d]imidazol-2-amine derivatives (5a-d and 6a-e) were effectively synthesised and testified for their molecular adaptations in order to develop them as novel medications against oxidation, inflammation and inflammation associated cancer types by means of in silico and in vitro assessments. Chronic inflammation, regardless of infectious agents, plays a vital role in various cancer development. Moreover, hypoxia-inflammation-cancer are highly associated together. Hydrogen peroxide free-radical scavenging, HRBC membrane stabilization assay and cell viability test by MTT assay (macrophage) were executed to establish antioxidant, anti-inflammatory and anticancer properties of these compounds. As the prostaglandin-endoperoxide synthase 2 is highly involved in inflammation and cancer development respectively, molecular docking was executed on the corresponding X-ray crystallographic models (PDB structures).

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Methylation of Methyl 4-Hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate: Synthetic, Crystallographic, and Molecular Docking Studies

Molecules ◽

10.3390/molecules25184238 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4238

Author(s):

Sergiy M. Kovalenko ◽

Oleksandr G. Drushlyak ◽

Svitlana V. Shishkina ◽

Irina S. Konovalova ◽

Illia O. Mariutsa ◽

...

Keyword(s):

Molecular Docking ◽

Combinatorial Libraries ◽

Docking Studies ◽

X Ray Diffraction ◽

Docking Simulations ◽

Design And Synthesis ◽

Hbv Replication ◽

Biological Studies ◽

Reliable Design

Consecutive alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate by CH3I has been investigated to establish regioselectivity of the reaction for reliable design and synthesis of combinatorial libraries. In the first stage, the product of S-methylation-methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate was obtained. The subsequent alkylation with CH3I led to the formation of both O- and N-methylation products mixture-methyl 4-methoxy-2-(methylthio)quinoline-3-carboxylate and methyl 1-methyl-2-(methylthio)-4-oxo-1,4-dihydroquinoline-3-carboxylate with a predominance of O-methylated product. The structure of synthesized compounds was confirmed by means of elemental analysis, 1H-NMR, 13C-NMR, LC/MS, and single-crystal X-ray diffraction. The quantum chemical calculations of geometry and electron structure of methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate’s anion were carried out. According to molecular docking simulations, the studied compounds can be considered as potent inhibitors of Hepatitis B Virus replication. Experimental in vitro biological studies confirmed that studied compounds demonstrated high inhibition of HBV replication in 10 µM concentration.

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α-Glucosidase Inhibition and Molecular Docking Studies of Natural Brominated Metabolites from Marine Macro Brown Alga Dictyopteris hoytii

Marine Drugs ◽

10.3390/md17120666 ◽

2019 ◽

Vol 17 (12) ◽

pp. 666 ◽

Cited By ~ 8

Author(s):

Najeeb Ur Rehman ◽

Kashif Rafiq ◽

Ajmal Khan ◽

Sobia Ahsan Halim ◽

Liaqat Ali ◽

...

Keyword(s):

Molecular Docking ◽

Brown Alga ◽

Docking Studies ◽

Spectroscopic Techniques ◽

Molecular Docking Studies ◽

Ethyl Methyl ◽

2D Noesy ◽

Ic50 Value ◽

Ic50 Values

Bioassay guided isolation of the methanolic extract of marine macro brown alga Dictyopteris hoytii afforded one new metabolite (ethyl methyl 2-bromobenzene 1,4-dioate, 1), one new natural metabolite (diethyl-2-bromobenzene 1,4-dioate, 2) along with six known metabolites (3–8) reported for the first time from this source. The structure elucidation of all these compounds was achieved by extensive spectroscopic techniques including 1D (1H and 13C) and 2D (NOESY, COSY, HMBC and HSQC) NMR and mass spectrometry and comparison of the spectral data of known compounds with those reported in literature. The in vitro α-glucosidase inhibition studies confirmed compound 7 to be the most active against α-glucosidase enzyme with IC50 value of 30.5 ± 0.41 μM. Compounds 2 and 3 demonstrated good inhibition with IC50 values of 234.2 ± 4.18 and 289.4 ± 4.91 μM, respectively, while compounds 1, 5, and 6 showed moderate to low inhibition. Furthermore, the molecular docking studies of the active compounds were performed to examine their mode of inhibition in the binding site of the α-glucosidase enzyme.

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Isolation of stigmasterol from hexane extract of leaves of Pisonia grandis R.Br, in vitro anti-diabetic and its molecular docking studies

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11i2.2158 ◽

2020 ◽

Vol 11 (2) ◽

pp. 2117-2122

Author(s):

Abhijit Mitra ◽

Mohankumar Ramasamy ◽

Valentina Parthiban ◽

Thottempudi Ravi Teja ◽

Srikalyani Vemuri ◽

...

Keyword(s):

Molecular Docking ◽

Docking Studies ◽

Hexane Extract ◽

Medicinal Uses ◽

Isolation And Purification ◽

Molecular Docking Studies ◽

Ic50 Value ◽

Isolated Compound ◽

Pisonia Grandis

Pisonia grandis R.Br belonging to the family Nyctaginaceae is a widely distributed evergreen tree in India known for its medicinal uses. The study was aimed to investigate the anti-diabetic property in the leaves of Pisonia grandis R.Br. The isolation and purification were performed by the conventional column chromatography and the resultant yield was found to be a white crystalline powder, which was further subjected for characterization through IR, 1H NMR, 13C NMR and Mass spectroscopy. From the characterization data, the isolated compound was identified as stigmasterol, it was first time isolated from the hexane extract of the leaves. The α-amylase inhibitory activity of stigmasterol from the hexane extract of the leaves of Pisonia grandis R.Br showed high potent activity with an IC50 value of 46μg/ml. The anti-diabetic activity of the compound against α-amylase and four other diabetic enzymes- α-glucosidase acid phosphatase, endo-β-N acetaglucosaminidase and β-glucuronidase were further investigated by molecular docking studies and proved that stigmasterol can be a potential anti-diabetic agent.

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Comparative Evaluation of the Cytotoxicity of Glyphosate-Based Herbicides and Glycine in L929 and Caco2 Cells

Frontiers in Public Health ◽

10.3389/fpubh.2021.643898 ◽

2021 ◽

Vol 9 ◽

Author(s):

Francesca Truzzi ◽

Daniele Mandrioli ◽

Federica Gnudi ◽

Paul T. J. Scheepers ◽

Ellen K. Silbergeld ◽

...

Keyword(s):

Amino Acid ◽

Trypan Blue ◽

Intestinal Microbiome ◽

Sprague Dawley ◽

Literature Report ◽

Cytotoxic Effects ◽

Caco2 Cells ◽

Ic50 Value

Introduction: Glyphosate, an amino acid analog of glycine, is the most widely applied organophosphate pesticide worldwide and it is an active ingredient of all glyphosate-based herbicides (GBHs), including the formulation “Roundup. ” While glycine is an essential amino acid generally recognized safe, both epidemiological and toxicological in vivo and in vitro studies available in literature report conflicting findings on the toxicity of GBHs. In our earlier in vivo studies in Sprague–Dawley rats we observed that exposure to GBHs at doses of glyphosate of 1.75 mg/kg bw/day, induced different toxic effects relating to sexual development, endocrine system, and the alteration of the intestinal microbiome. In the present work, we aimed to comparatively test in in vitro models the cytotoxicity of glycine and GBHs.Methods: We tested the cytotoxic effects of glycine, glyphosate, and its formulation Roundup Bioflow at different doses using MTT and Trypan Blue assays in human Caco2 and murine L929 cell lines.Results: Statistically significant dose-related cytotoxic effects were observed in MTT and Trypan Blue assays in murine (L929) and human (Caco2) cells treated with glyphosate or Roundup Bioflow. No cytotoxic effects were observed for glycine. In L929, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in both MTT and Trypan Blue assays. In Caco2, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in the MTT assays, while a comparable IC50 was observed for glyphosate and Roundup Bioflow in Trypan Blue assays. IC50 for glycine could not be estimated because of the lack of cytotoxic effects of the substance.Conclusion: Glyphosate and its formulation Roundup Bioflow, but not glycine, caused dose-related cytotoxic effects in in vitro human and murine models (Caco2 and L929). Our results showed that glycine and its analog glyphosate presented different cytotoxicity profiles. Glyphosate and Roundup Bioflow demonstrate cytotoxicity similar to other organophosphate pesticides (malathion, diazinon, and chlorpyriphos).

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