Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 123, P. 105770 - 105770

Published: April 2, 2022

Language: Английский

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Synthesis of New Organoselenium-Based Succinanilic and Maleanilic Derivatives and In Silico Studies as Possible SARS-CoV-2 Main Protease Inhibitors

Inorganics, Journal Year: 2023, Volume and Issue: 11(8), P. 321 - 321

Published: July 29, 2023

Herein we report the synthesis of organic selenide-based maleanilic and succinanilic acids in good yields (up to 95%). Their structural identities were elucidated by spectroscopic techniques (e.g., IR, 1H- & 13C-NMR, MS). The ADMET analysis, molecule electrostatic potential map, DFT, frontier molecular orbital used study organoselenium compounds’ pharmacokinetics, drug-likeness characteristics, geometries, chemical electronic properties. Moreover, a docking tool was employed investigate selenides’ ability inhibit SARS-CoV-2 Mpro target (PDB: 7BFB). Within this context, selenides exhibited promising binding affinities receptor following order (12 > 11 10 9 7 8). Furthermore, dynamics simulations also carried out for 200 ns evaluate exact behavior most active compound (12) within pocket compared with its co-crystallized inhibitor (Co).

Language: Английский

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Synthesis, structural characterization, DFT calculations, molecular docking, and molecular dynamics simulations of a novel ferrocene derivative to unravel its potential antitumor activity

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: unknown, P. 1 - 18

Published: June 8, 2022

In this article, we describe a set of subsequent five-steps chemical reactions to synthesize ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (compound 10). Structural characterization 10 and its intermediate products was also performed reported attest their formation. A molecular docking study propose the novel synthesized (10) as potential antitumor candidate targeting mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. The computed score at -9.50 kcal/mol compared native anticancer staurosporine -8.72 postulated promising activity. Also, dynamics (MD) simulations were carried out for 500 ns followed by MM-GBSA-binding free energy calculations both docked complexes give more deep insights into dynamic behavior in physiological conditions. Furthermore, DFT unravel some physiochemical characteristics (10). quantum mechanics shed light on structural electrochemical configurations which would open horizon further investigation. HighlightsThe synthesis 10) described.Structural characterizations performed.DFT calculations, docking, dynamics, MM-GBSA out.Computational studies revealed through inhibiting 1.Communicated Ramaswamy H. Sarma.

Language: Английский

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Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 777 - 792

Published: Dec. 16, 2022

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising inhibitors. Therefore, two novel series of pyridazine-linked cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized investigate the inhibitory activity candidates. Notably, 8e 9e exhibited best inhibition profiles. Moreover, showed strong antitumor effects against both MCF-7 A549 cell lines. The on cycle apoptosis measured. Besides, evaluated its in vivo using solid Ehrlich carcinoma. reduction tumor weight volume greater than doxorubicin. Also, molecular docking ADME studies performed. Finally, SAR study conducted gain further insights into different potentials upon variable structural modifications.

Language: Английский

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Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(20), P. 12235 - 12235

Published: Oct. 13, 2022

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated highest binding affinities towards Mpro. A dynamics study at 200 ns was also carried out for most promising anticoagulants to provide insights into dynamic thermodynamic properties compounds. Moreover, a quantum mechanical conducted which helped us attest some findings. biological evaluation (in vitro) compounds performed by carrying MTT cytotoxicity assay crystal violet order assess inhibitory concentration 50 (IC50). It is worth noting that displayed intrinsic potential inhibition with an IC50 value 5.60 µM safety index 25.33. addition, fondaparinux sodium dabigatran showed activities values 8.60 9.40 µM, respectively, indexes 17.60 15.10, respectively. Mpro enzyme investigated utilizing tipranavir as reference standard. Interestingly, attained 2.36 surpassing (IC50 = 7.38 µM) more than three-fold. Furthermore, highly eligible 10.59 µM. Finally, SAR discussed, counting on findings both vitro approaches.

Language: Английский

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A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval

Drug Design Development and Therapy, Journal Year: 2022, Volume and Issue: Volume 16, P. 685 - 715

Published: March 1, 2022

Abstract: The rising outbreak of SARS-CoV-2 continues to unfold all over the world. development novel effective antiviral drugs fight against is a time cost. As result, some specific FDA-approved have already been repurposed and authorized for COVID-19 treatment. used were either or non-antiviral drugs. Accordingly, present review thoroughly focuses on repurposing efficacy these including clinical trials experienced, combination therapies used, methods followed treatment, their future perspective. Therefore, drug was regarded as an avenue Recently, molnupiravir prodrug medication that approved in United Kingdom November 2021 treatment COVID-19. On other hand, PF-07321332 oral developed by Pfizer. For COVID-19, PF-07321332/ritonavir Phase III studies marketed Paxlovid. Herein, we represented almost history combating from recently available anti-SARS-CoV-2 candidates, new hope end current pandemic. Graphical Keywords: SARS-CoV-2, repurposing, trials, molnupiravir, paxlovid

Language: Английский

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Design and synthesis of novel benzoazoninone derivatives as potential CBSIs and apoptotic inducers: In Vitro, in Vivo, molecular docking, molecular dynamics, and SAR studies

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 127, P. 105995 - 105995

Published: June 30, 2022

Language: Английский

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Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice

Life Sciences, Journal Year: 2023, Volume and Issue: 316, P. 121390 - 121390

Published: Jan. 14, 2023

Language: Английский

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Ligand-based design and synthesis of N'-Benzylidene-3,4-dimethoxybenzohydrazide derivatives as potential antimicrobial agents; evaluation by in vitro, in vivo, and in silico approaches with SAR studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1098 - 1119

Published: April 18, 2022

Herein, a series of N'-benzylidene-3,4-dimethoxybenzohydrazide derivatives were designed and synthesised to target the multidrug efflux pump (MATE). The antibacterial activities screened against S. aureus, Acinetobacter, typhi, E. coli, P. aeruginosa, whereas their antifungal C. albicans. Compounds 4a, 4h, 4i showed most promising activities. Moreover, compounds 4h being broader superior members regarding antimicrobial effects selected be further evaluated via in vivo testing using biochemical analysis liver/kidney histological examination. Additionally, molecular docking was carried out attain deep insights into compounds' binding modes. Also, ADMET studies performed investigate physicochemical/pharmacokinetics features toxicity parameters derivatives. Finally, structure-antimicrobial activity relationship study established facilitate structural modifications future. HighlightsA new targeting (MATE) guided by pharmacophoric co-crystallized native inhibitor protein.The newly assessed through vitro, vivo, silico approaches.Using agar well diffusion assay, whereas, albicans.The minimal inhibitory concentration (MIC) bactericidal (MBC) investigated on variable microbial species.Compounds (4h 4i) -as effects- bio-chemical examination.A performed.A

Language: Английский

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A novel role of Nano selenium and sildenafil on streptozotocin-induced diabetic nephropathy in rats by modulation of inflammatory, oxidative, and apoptotic pathways

Life Sciences, Journal Year: 2022, Volume and Issue: 303, P. 120691 - 120691

Published: June 4, 2022

Language: Английский

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