Identification of Regioisomers in a Series of N-Substituted Pyridin-4-yl Imidazole Derivatives by Regiospecific Synthesis, GC/MS, and ¹H NMR

Abstract

The regiospecific synthesis of 2a (Scheme 3), a novel and potent pyridinyl imidazole inhibitor of p38 MAP (mitogen-activated protein) kinase, and the regioselective preparation of its regioisomer 2b (Scheme 4) are described. Chromatographic and spectroscopic data are presented, which in this class of compounds allow the unambiguous identification of regioisomers prepared by a nonregiospecific synthetic strategy. Biological data demonstrating the importance of the correct regiochemistry for inhibition of p38 are given.

Tetra-Substituted Pyridinylimidazoles As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase 3 for Potential Treatment of Neurodegenerative Diseases

“…The tetra-substituted imidazoles 6 bearing an Nacetyl moiety at the pyridine−C2-amino position were prepared using a versatile and diverse synthetic strategy starting from N-(4-(2-(4-fluorophenyl)-2-(hydroxyimino)acetyl)pyridin-2-yl)-acetamide (3a) 24 (Scheme 1) that has been developed in our group. 16−19 This synthesis allows the introduction of a broad variety of aliphatic and functionalized moieties at the imidazole− N1 as well as the imidazole−C2-S position.…”

Imidazole and Benzimidazole Derivatives as Chemotherapeutic Agents

“…Regioselective functionalization of imidazole at position 2, 4 and 5 has been possible through a directed lithiation and metal-halogen exchange methodology [21,22]. Remarkably, imidazole N-oxides are useful intermediates in the synthesis of structurally diverse imidazoles [23,24] (Scheme 2).…”

Synthesis and Biological Testing of N‐Aminoimidazole‐Based p38α MAP Kinase Inhibitors

“…[25,26,28] Attempts to prepare suitably substituted triazinanes failed. Therefore, a novel synthesis was developed to construct N-[4-(4-fluorophenyl)-2-methylthio-5-(pyridin-4-yl)-1H-imidazol-1-yl]amide compounds.…”