1. Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N‐formyl peptide receptors agonists
- Author
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Agostino Cilibrizzi, Niccolò Cantini, Liliya N. Kirpotina, Andrei I. Khlebnikov, Mark T. Quinn, Letizia Crocetti, Gabriella Guerrini, Maria Paola Giovannoni, Claudia Vergelli, Paola Paoli, Igor A. Schepetkin, and Patrizia Rossi
- Subjects
Agonist ,Models, Molecular ,Molecular model ,medicine.drug_class ,Stereochemistry ,Neutrophils ,Pyridones ,pyrazolone ,Pyrazolone ,Peptide ,Pyrazole ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Acetamides ,medicine ,cancer ,Humans ,Pyrazolones ,Receptor ,Oxazoles ,Research Articles ,Pharmacology ,chemistry.chemical_classification ,formyl peptide receptor ,Formyl peptide receptor ,Binding Sites ,Chemistry ,Organic Chemistry ,neutrophil ,Triazoles ,Receptors, Formyl Peptide ,pyrazole ,inflammation ,Molecular Medicine ,Pyrazoles ,Acetamide ,medicine.drug ,Research Article ,Protein Binding - Abstract
N‐formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4‐(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6‐membered compounds, all exhibiting the same 4‐bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five‐membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site., N‐formyl peptide receptors (FPRs) play key roles in inflammation and cancer. The present paper reports a new series of pyrazole and pyrazolone derivatives as potential FPRs agonists, containing the 4‐(bromophenyl)acetamide fragment that was essential for activity in all our previous synthesized compounds. Molecular modeling studies, performed using the first FPR2 co‐crystallized protein, highlighted that the five‐member nucleous is responsible for a worse arrangement of the key fragment (4‐bromophenyl‐2‐acetamide chain) in the receptor binding site.
- Published
- 2021