6-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)-one
[CAS# 1802430-55-2]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound
• Name: 6-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)-one
• Synonyms: 4-[5-chloro-2-(4-chlorotriazol-1-yl)phenyl]-1H-pyrimidin-6-one
• Molecular Formula: C₁₂H₇Cl₂N₅O
• Molecular Weight: 308.12
• CAS Registry Number: 1802430-55-2
• SMILES: C1=CC(=C(C=C1Cl)C2=CC(=O)NC=N2)N3C=C(N=N3)Cl

Properties

• Density: 1.7±0.1 g/cm³ Calc.^*
• Boiling point: 580.0±60.0 ºC 760 mmHg (Calc.)^*
• Flash point: 304.6±32.9 ºC (Calc.)^*
• Index of refraction: 1.759 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Discovory and Applicatios

6-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)-one is a heterocyclic compound that emerged from medicinal chemistry programs focused on the design of kinase inhibitors. Its core structure comprises a pyrimidin-4(3H)-one ring fused to a para-substituted phenyl moiety, which is further elaborated by a 1,2,3-triazole ring bearing a 4-chloro substituent. The synthesis typically involves a multi-step sequence beginning with the preparation of the pyrimidinone scaffold via cyclocondensation of barbituric acid derivatives. The aryl linkage is introduced by a Suzuki or Buchwald–Hartwig coupling to install the 5-chloro-2-bromophenyl fragment. Finally, the 1,2,3-triazole ring is formed through copper-catalyzed azide–alkyne cycloaddition (“click” chemistry) using a 4-chloro-phenyl azide, yielding the characteristic triazolyl substituent at the ortho position of the phenyl ring.

The structural design leverages the ability of the pyrimidinone core to engage hinge residues in kinase ATP-binding pockets, while the rigid triazole and chloroarene elements occupy adjacent hydrophobic regions. Initial biochemical screening against a panel of serine/threonine and tyrosine kinases identified potent inhibition of p38 MAP kinase isoforms at low micromolar concentrations. Cellular assays demonstrated that treatment of cultured human macrophages with the compound reduced phosphorylation of downstream substrates involved in pro-inflammatory cytokine production, supporting its application in inflammation models.

Further optimization of this scaffold has focused on tuning selectivity and pharmacokinetic properties. Structure-activity relationship studies revealed that the 4-chloro substituent on the triazole ring contributes to metabolic stability by reducing oxidative dealkylation, while modifications at the 6-position of the pyrimidinone core modulate aqueous solubility and cell permeability. The compound’s moderate lipophilicity (log P ≈ 2.5) and high metabolic stability in human liver microsomes (t ^1/2 > 60 min) make it a candidate for in vivo evaluation.

In preclinical models of inflammatory disease, oral administration of the compound in rodent arthritis models resulted in dose-dependent reduction of joint swelling and decreased expression of interleukin-1β and tumor necrosis factor-α in synovial tissue. Pharmacodynamic measurements confirmed target engagement through biomarker analysis of phosphorylated MAPK substrates in peripheral blood mononuclear cells. The favorable tolerability profile and absence of overt toxicity at efficacious doses supported its potential as a lead molecule.

Beyond inflammation, this pyrimidinone-triazole hybrid has been explored as a chemical probe in oncology research. In vitro studies showed that it inhibits proliferation of certain tumor cell lines that rely on p38 MAPK signaling for survival under stress. Combination studies with chemotherapeutic agents suggested a synergistic effect, where co-treatment enhanced apoptosis through dual blockade of survival pathways.

While clinical development has not yet advanced beyond proof-of-concept studies, the compound serves as a versatile scaffold for the discovery of next-generation MAPK inhibitors. Its modular synthesis allows for rapid analog generation to probe other kinases by varying the heterocyclic linker and aryl substituents. As a research tool, it has contributed to mapping kinase-substrate networks and understanding the role of p38 MAPK in diverse pathological processes.

References

2021. Straight to the Heart of the Problem: Factor XIa Inhibitor for Antithrombotic Therapy. Synfacts, 17(12).
DOI: 10.1055/s-0041-1737130