Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists

Claudia Vergelli; Andrei I. Khlebnikov; Letizia Crocetti; Gabriella Guerrini; Niccolò Cantini; Liliya N. Kirpotina; Igor A. Schepetkin; Agostino Cilibrizzi; Mark T. Quinn; Patrizia Rossi; Paola Paoli; Maria Paola Giovannoni

doi:10.1111/cbdd.13913

Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists

Claudia Vergelli, Andrei I. Khlebnikov, Letizia Crocetti^*, Gabriella Guerrini, Niccolò Cantini, Liliya N. Kirpotina, Igor A. Schepetkin, Agostino Cilibrizzi, Mark T. Quinn, Patrizia Rossi, Paola Paoli, Maria Paola Giovannoni

^*Corresponding author for this work

Institute of Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Pages (from-to)	582-603
Number of pages	22
Journal	Chemical Biology and Drug Design
Volume	98
Issue number	4
DOIs	https://doi.org/10.1111/cbdd.13913
Publication status	Published - Oct 2021

Keywords

Agonist
cancer
formyl peptide receptor
inflammation
neutrophil
pyrazole
pyrazolone

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1111/cbdd.13913

Cite this

Vergelli, C., Khlebnikov, A. I., Crocetti, L., Guerrini, G., Cantini, N., Kirpotina, L. N., Schepetkin, I. A., Cilibrizzi, A., Quinn, M. T., Rossi, P., Paoli, P., & Giovannoni, M. P. (2021). Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists. Chemical Biology and Drug Design, 98(4), 582-603. https://doi.org/10.1111/cbdd.13913

@article{5caea3d54f4041508399f7aa431f923b,

title = "Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists",

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.",

keywords = "Agonist, cancer, formyl peptide receptor, inflammation, neutrophil, pyrazole, pyrazolone",

author = "Claudia Vergelli and Khlebnikov, {Andrei I.} and Letizia Crocetti and Gabriella Guerrini and Niccol{\`o} Cantini and Kirpotina, {Liliya N.} and Schepetkin, {Igor A.} and Agostino Cilibrizzi and Quinn, {Mark T.} and Patrizia Rossi and Paola Paoli and Giovannoni, {Maria Paola}",

note = "Funding Information: This study was supported by the National Institutes of Health National Institutes of Health IDeA Program Grants GM115371 and GM103474 and the Tomsk Polytechnic University Competitiveness Enhancement Program (project TPU CEP‐SAMT‐208/2020). Publisher Copyright: {\textcopyright} 2021 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = oct,

doi = "10.1111/cbdd.13913",

language = "English",

volume = "98",

pages = "582--603",

journal = "Chemical Biology & Drug Design",

issn = "1747-0277",

publisher = "Blackwell",

number = "4",

}

Vergelli, C, Khlebnikov, AI, Crocetti, L, Guerrini, G, Cantini, N, Kirpotina, LN, Schepetkin, IA, Cilibrizzi, A, Quinn, MT, Rossi, P, Paoli, P & Giovannoni, MP 2021, 'Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists', Chemical Biology and Drug Design, vol. 98, no. 4, pp. 582-603. https://doi.org/10.1111/cbdd.13913

Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists. / Vergelli, Claudia; Khlebnikov, Andrei I.; Crocetti, Letizia et al.

In: Chemical Biology and Drug Design, Vol. 98, No. 4, 10.2021, p. 582-603.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists

AU - Vergelli, Claudia

AU - Khlebnikov, Andrei I.

AU - Crocetti, Letizia

AU - Guerrini, Gabriella

AU - Cantini, Niccolò

AU - Kirpotina, Liliya N.

AU - Schepetkin, Igor A.

AU - Cilibrizzi, Agostino

AU - Quinn, Mark T.

AU - Rossi, Patrizia

AU - Paoli, Paola

AU - Giovannoni, Maria Paola

N1 - Funding Information: This study was supported by the National Institutes of Health National Institutes of Health IDeA Program Grants GM115371 and GM103474 and the Tomsk Polytechnic University Competitiveness Enhancement Program (project TPU CEP‐SAMT‐208/2020). Publisher Copyright: © 2021 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

KW - Agonist

KW - cancer

KW - formyl peptide receptor

KW - inflammation

KW - neutrophil

KW - pyrazole

KW - pyrazolone

UR - http://www.scopus.com/inward/record.url?scp=85114847892&partnerID=8YFLogxK

U2 - 10.1111/cbdd.13913

DO - 10.1111/cbdd.13913

M3 - Article

C2 - 34148303

AN - SCOPUS:85114847892

SN - 1747-0277

VL - 98

SP - 582

EP - 603

JO - Chemical Biology & Drug Design

JF - Chemical Biology & Drug Design

IS - 4

ER -

Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this