Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity

Mohamed, Fatma A.M.; Gomaa, Hesham A.M.; Hendawy, Omnia M.; Ali, Asmaa T.; Farghaly, Hatem S.; Gouda, Ahmed M.; Abdelazeem, Ahmed H.; Abdelrahman, Mostafa H.; Trembleau, Laurent; Youssif, Bahaa G.M.

doi:10.1016/j.bioorg.2021.104960

Cited by 55 publications

(48 citation statements)

References 47 publications

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“…Nunes et al [112] also reported a facile synthesis of 18 F-labeled lapatinib that can be Among the proposed metabolites, pyridinium salt M5 was formed from the bioactivation of the furane ring, an intramolecular cyclization. The hydroxypyridine metabolite M2 was formed from M5 after the loss of the ethyl sulfone moiety from M5.…”

Section: Metabolismmentioning

confidence: 99%

“…Nunes et al [112] also reported a facile synthesis of 18 F-labeled lapatinib that can be used in pharmacokinetic evaluation. In addition, Saleem et al [113] reported the synthesis of [ 11 C] lapatinib-PET.…”

Section: Metabolismmentioning

confidence: 99%

“…These crystal structures provide a huge amount of information that enables researchers in this field to understand the structure and function of the EGFR. This must enhance the discovery and development of rationally designed EGFR tyrosine kinase inhibitors [17][18][19]. Discovery Studio Visualizer [16] was used to generate the binding modes/interactions figures of all the EGFR inhibitors discussed in this review.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

et al. 2021

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Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

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Section: Metabolismmentioning

confidence: 99%

Section: Metabolismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

et al. 2021

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“…[ 46 ]. Preparation of ligands/protein files [ 49 ], grid, and docking parameters files [ 49 , 50 ] was done following the previous reports. The crystal structures of the six proteins were obtained from the protein data bank.…”

Section: Methodsmentioning

confidence: 99%

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

et al. 2021

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In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC50 = 0.01–40.50 μM) and one normal MRC5 (IC50 = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC50 = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G2/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.

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New 1,2,4‐oxadiazole/pyrrolidine hybrids as topoisomerase IV and DNA gyrase inhibitors with promising antibacterial activity

Frejat

Cao

Wang

et al. 2022

Archiv der Pharmazie

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A series of hybridized pyrrolidine compounds with a 1,2,4‐oxadiazole moiety were synthesized to develop effective molecules against the enzymes DNA gyrase and topoisomerase IV (Topo IV). Compounds 8–20 were developed based on a previously disclosed series of compounds from our lab, but with small structural modifications in the hopes of increasing the compounds' biological activity. In comparison to novobiocin, with IC50 = 170 nM, the findings of the DNA gyrase inhibitory assay revealed that compounds 16 and 17 were the most potent of all synthesized derivatives, with IC50 values of 180 and 210 nM, respectively. Compound 17 had the strongest inhibitory effect against Escherichia coli Topo IV of all the synthesized compounds, with an IC50 value of 13 µM, which was comparable to novobiocin (IC50 = 11 µM). Therefore, hybrids 16 and 17 appeared to be potential dual‐target inhibitors. In the minimal inhibitory concentration (MIC) assays, compound 17 outperformed ciprofloxacin against E. coli, with an MIC of 55 ng/ml, compared to 60 ng/ml for ciprofloxacin. Finally, the docking study, along with the in vitro experiments, supports our promising approach to effectively develop potent leads for further optimization as dual DNA gyrase and Topo IV inhibitors.

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Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity

Cited by 55 publications

References 47 publications

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

New 1,2,4‐oxadiazole/pyrrolidine hybrids as topoisomerase IV and DNA gyrase inhibitors with promising antibacterial activity

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