The antimicrobial potential and pharmacokinetic profiles of novel quinoline-based scaffolds: synthesis and <i>in silico</i> mechanistic studies as dual DNA gyrase and DHFR inhibitors

El-Shershaby, Mohamed H.; El‐Gamal, Kamal M.; Bayoumi, Ashraf H.; El‐Adl, Khaled; Alswah, Mohamed; Ahmed, Hany E. A.; Al-Karmalamy, Ahmed A.; Abulkhair, Hamada S.

doi:10.1039/d1nj02838c

Cited by 52 publications

(35 citation statements)

References 72 publications

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“…The 3D structures of the isolated identified four compounds (ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4) were downloaded from the PubChem database and prepared for docking following the preparation steps described earlier [66][67][68]. Here, they were introduced into the MOE window, subjected to partial charges addition, and energy minimized [69,70]. Then, the prepared compounds were inserted into one database with the co-crystallized inhibitor (N3) and saved as an MDB file to be uploaded in the ligand icon during the docking step.…”

Section: The Isolated and Identified Four Compounds (1-4) Preparationmentioning

confidence: 99%

Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

et al. 2021

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In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were isolated from the leaves of Pimenta dioica (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (1–4) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC50) and SARS-CoV-2 inhibitory concentrations (IC50). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with P. dioca aqueous extract, ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin 2, gallic acid 3, and chlorogenic acid 4 showed remarkable anti-SARS-CoV-2 activities with IC50 values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid 1 and rutin 2 treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin 2 either alone or in combination with other isolates for COVID-19 management.

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Section: The Isolated and Identified Four Compounds (1-4) Preparationmentioning

confidence: 99%

Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

et al. 2021

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“…The adopted synthetic strategies for the preparation of target compounds (4-7) are shown in Schemes 1 and 2. The synthesis was initiated by cyclocondensation of 2-benzoylbenzoic acid (1) with hydrazine hydrate to afford the corresponding 4-phenylphthalazin-1(2H)-one [11,47,48] (2), which underwent chlorination by reaction with phosphorous oxychloride [11,33,49] to afford 1-chloro-4phenylphthalazine (3). The chloro derivative 3 was heated under reflux with the 4-aminoacetophenone to afford the corresponding acetyl derivative 4.…”

Section: Chemistrymentioning

confidence: 99%

“…The chloro derivative 3 was heated under reflux with the 4-aminoacetophenone to afford the corresponding acetyl derivative 4. On the contrary, the acetyl derivative 4 was condensed with the appropriate benzaldehyde to yield the corresponding chalcone derivatives 5 a-g following the reported procedure [47,48,50] (Scheme 1). The produced chalcone derivatives 5 a-g underwent binucleophilic cyclocondensation reactions with hydrazine hydrate and/or urea [51,52] to yield the corresponding pyrazoline 6 a-g and/or pyrimidin-2(1H)-one 7 a-c , respectively (Scheme 2).…”

Section: Chemistrymentioning

confidence: 99%

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Khedr

Ibrahim

Eissa

et al. 2021

Archiv der Pharmazie

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In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR‐2 inhibitory potential, including an α,β‐unsaturated ketonic fragment, pyrazole, and pyrimidine. Also, new distal hydrophobic moieties were attached to these linkers that are expected to increase the hydrophobic interaction with VEGFR‐2 and, consequently, the affinity. These structural optimizations have led us to identify the novel dihydropyrazole derivative 6e as a promising hit molecule. All the new derivatives were evaluated to assess their anticancer activity against three human cancer cell lines, including HepG2, HCT‐116, and MCF‐7. The results of the in vitro anticancer evaluation study revealed the moderate to excellent cytotoxicity of 6c, 6e, 6g, and 7b, with IC50 values in the low micromolar range. The inhibitory activity of VEGFR‐2 was investigated for 16 of the designed compounds. The enzyme assay results of the new compounds were compared with those of sorafenib as a reference VEGFR‐2 inhibitor. The obtained results demonstrated that our derivatives are potent VEGFR‐2 inhibitors. The most potent derivatives 6c, 6e, 6g, and 7b showed IC50 values in the range of 0.11–0.22 µM. Molecular docking and pharmacokinetic studies were also conducted to rationalize the VEGFR‐2 inhibitory activity and to evaluate the ability of the most potent derivatives to be developed as good drug candidates.

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“…Also, the general docking specications were selected to be triangle matcher, London dG, GBVI/WSA dG, and rigid receptor for the placement methodology, rst scoring methodology, nal scoring methodology, and renement methodology, respectively. [71][72][73] Aer completion of the docking process, the best pose for each examined compound-according to the score and RMSD values-was selected for further investigations.…”

Section: Molecular Docking Studymentioning

confidence: 99%

Investigating the structure–activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors

et al. 2021

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The antimicrobial potential and pharmacokinetic profiles of novel quinoline-based scaffolds: synthesis and in silico mechanistic studies as dual DNA gyrase and DHFR inhibitors

Abstract: The resistance of pathogenic microbes to currently available antimicrobial agents has been considered a global alarming concern.

Cited by 52 publications

References 72 publications

Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Investigating the structure–activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors

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