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Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors.

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Bibliographic Details
Title: Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors.
Authors: Al-Wahaibi LH; Department of Chemistry, College of Sciences, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia., Abou-Zied HA; Medicinal Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt., Mahmoud MA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Youssif BGM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Bräse S; Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, Karlsruhe, Germany., Rabea SM; Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt.; Apogee Pharmaceuticals, Burnaby, BC, Canada.
Source: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2025 Dec; Vol. 40 (1), pp. 2516075. Date of Electronic Publication: 2025 Jun 24.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Taylor & Francis Country of Publication: England NLM ID: 101150203 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1475-6374 (Electronic) Linking ISSN: 14756366 NLM ISO Abbreviation: J Enzyme Inhib Med Chem Subsets: MEDLINE
Imprint Name(s): Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
MeSH Terms: ErbB Receptors*/antagonists & inhibitors , ErbB Receptors*/metabolism , Vascular Endothelial Growth Factor Receptor-2*/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2*/metabolism , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemical synthesis , Antineoplastic Agents*/chemistry , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemical synthesis , Protein Kinase Inhibitors*/chemistry , Drug Design* , Indazoles*/chemistry , Indazoles*/pharmacology , Indazoles*/chemical synthesis , Hydrazines*/pharmacology , Hydrazines*/chemistry , Hydrazines*/chemical synthesis, Humans ; Cell Proliferation/drug effects ; Structure-Activity Relationship ; Drug Screening Assays, Antitumor ; Molecular Structure ; Dose-Response Relationship, Drug ; Molecular Docking Simulation ; Apoptosis/drug effects ; Cell Line, Tumor
Abstract: A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a-o , serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds 7a-o were assessed against four cancer cell lines via the MTT assay. Compounds 7g , 7i-7l , and 7o emerged as the most efficient six derivatives, with GI 50 values ranging from 25 nM to 42 nM. Compounds 7j , 7k , and 7o (GI 50 values of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI 50 value of 33 nM), particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these new compounds. Computational analyses, encompassing molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) computations, elucidated the binding interactions of these drugs with EGFR and VEGFR-2.
Contributed Indexing: Keywords: Apoptosis; DFT; EGFR; VEGFR-2; cancer
Substance Nomenclature: EC 2.7.10.1 (ErbB Receptors)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
EC 2.7.10.1 (EGFR protein, human)
0 (Indazoles)
EC 2.7.10.1 (KDR protein, human)
0 (Hydrazines)
Entry Date(s): Date Created: 20250625 Date Completed: 20250625 Latest Revision: 20250625
Update Code: 20250625
DOI: 10.1080/14756366.2025.2516075
PMID: 40556275
Database: MEDLINE
Description
Abstract:A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a-o , serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds 7a-o were assessed against four cancer cell lines via the MTT assay. Compounds 7g , 7i-7l , and 7o emerged as the most efficient six derivatives, with GI <subscript>50</subscript> values ranging from 25 nM to 42 nM. Compounds 7j , 7k , and 7o (GI <subscript>50</subscript> values of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI <subscript>50</subscript> value of 33 nM), particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these new compounds. Computational analyses, encompassing molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) computations, elucidated the binding interactions of these drugs with EGFR and VEGFR-2.
ISSN:1475-6374
DOI:10.1080/14756366.2025.2516075