Pharmacophore‐linked pyrazolo[3,4‐<i>d</i>]pyrimidines as EGFR‐TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies

Gaber, Abd El‐Aal M.; El-Morsy, Ahmed; Sherbiny, Farag F.; Bayoumi, Ashraf H.; El‐Gamal, Kamal M.; El‐Adl, Khaled; Al‐Karmalawy, Ahmed A.; Eldin, Rogy R. Ezz; Saleh, Marwa A.; Abulkhair, Hamada S.

doi:10.1002/ardp.202100258

Cited by 53 publications

(39 citation statements)

References 59 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].…”

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 pharmacokinetic and physicochemical investigation is an outstanding step in identifying novel candidates from a hit to a drug 94–96 . So, the Swiss Institute of Bioinformatics (SIB) supplies the free Swiss ADME evaluating the physicochemical, pharmacokinetic, and ADME parameters of the synthesised candidates could be predicted as well.…”

Section: Methodsmentioning

confidence: 99%

Ligand-based design, synthesis, computational insights, andin vitrostudies of novelN-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease

Elagawany

Elmaaty

Mostafa

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of N -(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle of the SARS-CoV Mpro co-crystallized WR1 inhibitor. Notably, compound 3b achieved the most promising anti-SARS-CoV-2 activity with an IC 50 value of 174.7 µg/mL. On the other hand, compounds 3a , 3b , and 3c showed very promising SARS-CoV-2 Mpro inhibitory effects with IC 50 values of 4.67, 5.12, and 11.90 µg/mL, respectively. Compound 3b docking score was very promising (−6.94 kcal/mol) and its binding mode was nearly similar to that of WR1. Besides, the molecular dynamics (MD) simulations of compound 3b showed its great stability inside the binding pocket until around 40 ns. Finally, a very promising SAR was concluded to help to design more powerful SARS-CoV-2 Mpro inhibitors shortly.

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“…The physicochemical and pharmacokinetic characteristics investigation is a critical step in the synthesis of novel molecular entities from a hit to a drug 18 , 104–107 . Thereby, the Swiss Institute of Bioinformatics (SIB) supplies the free Swiss ADME web tool which can be used to evaluate physicochemical characteristics, and anticipate the ADME parameters and pharmacokinetic features of the newly synthesised compounds as well.…”

Section: Methodsmentioning

confidence: 99%

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

Eldin

Saleh

Alotaibi

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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

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Pharmacophore‐linked pyrazolo[3,4‐d]pyrimidines as EGFR‐TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies

Cited by 53 publications

References 59 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

Ligand-based design, synthesis, computational insights, andin vitrostudies of novelN-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease

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

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