Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry
Abstract
:1. Introduction
2. 3-Pyrazolyl-Ureas Derivatives
2.1. 3-Pyrazolyl-Ureas as Human Carbonic Anhydrase Inhibitors
2.2. 3-Pyrazolyl-Ureas as Cannabinoid Receptor Antagonist
2.3. 3-Pyrazolyl-Ureas as Antibacterial Agents
3. 4-Pyrazolyl-Ureas Derivatives
3.1. 4-Pyrazolyl-Ureas as Epoxide Hydrolase (sEH) Inhibitors
3.2. 4-Pyrazolyl-Ureas as Antiepileptic Drugs
3.3. 4-Pyrazolyl-Ureas as Anti-Inflammatory Agents
3.4. 4-Pyrazolyl-Ureas as Protein Kinases Inhibitors
3.4.1. CDK8 Inhibitors
3.4.2. RAS/RAF/MEK/ERK-MAPK Inhibitors
3.4.3. JNK Inhibitors
3.5. 4-Pyrazolyl-Ureas as Anticancer Agents
4. 5-Pyrazolyl-Ureas
4.1. 5-Pyrazolyl-Ureas as p38MAPK Inhibitors
4.2. 5-Pyrazolyl-Ureas Interfering with Neutrophil Migration
4.3. 5-Pyrazolyl-Ureas as Antiangiogenic Agents
4.4. 5-Pyrazolyl-Ureas as Anticancer Agents
4.5. 5-Pyrazolyl-Ureas as TrKA Inhibitors
4.6. 5-Pyrazolyl-Ureas as Antimalarial Agents
4.6.1. Antimalarial Agents acting as Protein-Protein Interaction Inhibitors
4.6.2. Antimalarial Agents Acting as PfATP4 Inhibitors
4.6.3. Antimalarial Agents Acting as P. falciparum Prolyl-tRNA-synthetase Inhibitors
- in N1 is needed the methyl group; NH, or polar substituents are not tolerated;
- the trifluoromethyl substituent in position 3 of the pyrazole acts as vector to the solvent and its removal is not tolerated, while more polar groups (such an example 2-ethyl-morpholine) causes a potency decrease;
- removal of the p-fluorophenyl moiety in position 4 of the pyrazole led to inactive compounds, but substitution in the phenyl ring could be changed without affecting the potency.
4.7. 5-Pyrazolyl-Ureas as Anti-Toxoplasma Agents
4.8. 5-Pyrazolyl-Ureas as Antibacterial Agents
4.9. 5-Pyrazolyl-Ureas as Anti-Trypanosome Agents
4.10. 5-Pyrazolyl-Ureas as Antiviral Agents
4.11. 5-Pyrazolyl-Ureas as Potassium Channel Activators
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
3D-QSAR | Three-dimensional quantitative SAR |
aaRS | Aminoacyl-tRNA synthase |
Abl | Abelson kinase |
AD | Alzheimer’s disease |
ALS | Amyotrophic lateral sclerosis |
AUDA | 12-(1-Adamantan-1-ylureido)- dodecanoic acid |
CAMK | Ca2+/calmodulin- dependent protein kinase |
CB1/2 | Cannabinoid receptors 1/2 |
CDK8/CycC | Cyclin-dependent kinase 8 and cyclin C |
COMFA | Comparative molecular field analysis |
CoMSIA | Comparative molecular similarity |
COPD | Chronic obstructive pulmonary disease |
COX-2 | Cyclooxygenase-type 2 |
CXCL8 | Interleukin 8 |
CXCR1/R2 | CXC Chemokine receptors 1/2 |
DFG (DMG) | Asp-Phe-Gly motif |
DMPK1 | Dystrophia myotonica protein kinase 1 |
ERK | extracellular-regulated protein kinase |
Flt3 | Fms related tyrosine kinase 3 |
fMLP | N-formyl-methionyl-leucyl-phenylalanine |
GIRK | G protein-gated inwardly-rectifying potassium channels |
GSK3α | Glycogen synthase kinases type 3α |
hCA II | Human carbonic anhydrase II |
hCAIs | Human carbonic anhydrase inhibitors |
Hck | Hemopoietic Cell Kinase |
HD | Huntington’s disease |
HeLa | Henrietta Lacks immortal cells |
hERG | Human Ether-à-go-go-Related Gene |
HFF | Human foreskin fibroblasts |
HSB | Hybrid structure based (virtual screening approach) |
HTS | High-throughput screening |
HUVEC | Human umbilical vein endothelial cells |
I-κB | Inhibitor of kappa B kinase |
IKK (1/2) | IkB kinases type 1/2 |
IL-1-/6/-17/-18 | Interleukin type 1/6/17/18 |
JM | Juxta-membrane |
JNK | c-Jun NH2-terminal kinase |
LPS | Lipopolysaccharide |
MAPK | Mitogen-activated protein kinase |
MBC | Minimum Bactericidal concentration |
MES | Maximal electroshock seizure |
MetRS | Methionyl-t-RNA synthetase |
MFC | Minimum fungicidal concentration |
MI | Myocardial infarction |
MIC | Minimum inhibiting concentration |
MLSCN | Molecular libraries screening center network |
MLSMR | Molecular libraries small molecule repository |
MS | Multiple sclerosis |
MTIP | Myosin tail interacting protein |
MyoA | Myosin A |
NEK10 | NIMA (never in mitosis gene a)-related kinase 10 |
NF-κΒ | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NGF | Nerve growth factor |
ONIOM | N-Layered integrated molecular orbital & molecular mechanics |
Panc-1 | Human pancreatic adenocarcinoma |
PD | Parkinson’s disease |
PDB | Protein data bank |
PDGFR | Platelet derived growth factor |
PfATP4 | Plasmodium falciparum p-type cation ATPase |
PfProRS | Plasmodium falciparum prolyl-t-RNA-synthetase |
PI3K | Protein inositol kinase 3 |
PKC | Protein kinase C |
PLK2, PLK3 | Polo-like kinase 2/3 |
PPI | Protein-protein interaction |
PTZ | Pentylenetetrazol-induced seizure |
RAF/RAS | Rapidly accelerated Fibrosarcoma |
RSV | Respiratory syncytial virus |
SAR | Structure Activity Relationship |
sEH | Soluble epoxide hydrolases |
SUMO | Small ubiquitin-like modifier |
Syk | Spleen tyrosine kinase |
TNF-α | Tumor necrosis factor alpha |
Trk | Tropomyosin receptor kinase |
UBSAs | Ureido benzenesulfonamides |
VEGF | Vascular endothelial growth factor |
VEGFR1/2 | Vascular endothelial growth factor receptor |
Zap-70 | Zeta Chain of T Cell Receptor Associated Protein Kinase 70 |
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Affinity Ki (nM) | Selectivity | ||
---|---|---|---|
Comp. 4 | CB1 | CB2 | CB1 |
a | 9 | 4920 | 546.7 |
b | 29 | 10863 | 374.6 |
c | 6.8 | 4319 | 635.2 |
d | 26 | 21791 | 838.1 |
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Brullo, C.; Rapetti, F.; Bruno, O. Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry. Molecules 2020, 25, 3457. https://doi.org/10.3390/molecules25153457
Brullo C, Rapetti F, Bruno O. Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry. Molecules. 2020; 25(15):3457. https://doi.org/10.3390/molecules25153457
Chicago/Turabian StyleBrullo, Chiara, Federica Rapetti, and Olga Bruno. 2020. "Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry" Molecules 25, no. 15: 3457. https://doi.org/10.3390/molecules25153457