Back to Search
Start Over
Discovery of novel pyrazole based Urea/Thiourea derivatives as multiple targeting VEGFR-2, EGFR WT , EGFR T790M tyrosine kinases and COX-2 Inhibitors, with anti-cancer and anti-inflammatory activities.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Jun; Vol. 147, pp. 107403. Date of Electronic Publication: 2024 Apr 27. - Publication Year :
- 2024
-
Abstract
- A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFR <superscript>WT</superscript> , EGFR <superscript>T790M</superscript> tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04-47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC <subscript>50</subscript>  = 5.0-7.50, 6.23-8.93 respectively, compared to celecoxib IC <subscript>50</subscript>  = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63-87.02 %, 98.98-43.10 % and 98.68-23.62 % respectively, and with GI <subscript>50</subscript> values of 1.76-15.50 µM, 1.60-5.38 µM, 1.68-7.39 µM and 1.81-11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC <subscript>50</subscript> of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC <subscript>50</subscript>  = 85 nM), and had excellent EGFR <superscript>WT</superscript> and EGFR <superscript>T790M</superscript> kinase inhibitory activities (IC <subscript>50</subscript>  = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC <subscript>50</subscript>  = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFR <superscript>wt</superscript> /EGFR <superscript>T790M</superscript> S.I.) of (range: 4.44-9.40) compared to erlotinib (2.03) and osmertinib (1.89).<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Structure-Activity Relationship
Molecular Structure
Cyclooxygenase 2 Inhibitors pharmacology
Cyclooxygenase 2 Inhibitors chemistry
Cyclooxygenase 2 Inhibitors chemical synthesis
Cell Line, Tumor
Cyclooxygenase 2 metabolism
Drug Discovery
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Anti-Inflammatory Agents, Non-Steroidal chemistry
Anti-Inflammatory Agents, Non-Steroidal chemical synthesis
Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors chemical synthesis
Pyrazoles chemistry
Pyrazoles pharmacology
Pyrazoles chemical synthesis
Drug Screening Assays, Antitumor
Cell Proliferation drug effects
Thiourea pharmacology
Thiourea chemistry
Thiourea chemical synthesis
Urea pharmacology
Urea chemistry
Urea analogs & derivatives
Dose-Response Relationship, Drug
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 147
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38691909
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107403