An Improved Method for the Synthesis of Dissymmetric N,N‘-Disubstituted Imidazole-4,5-dicarboxamides

Abstract

Symmetrically and dissymmetrically disubstituted imidazole-4,5-dicarboxamides (I45DCs) have diverse bioactivities and therefore represent useful small molecules for lead structure identification in drug discovery. For this reason, an improved synthesis was developed as a first step in the preparation of greater numbers of analogues. The method involves the transformation of imidazole-4,5-dicarboxylic acid into dissymmetrically disubstituted I45DCs in four steps and in a minimum yield of 51%. This reflects an overall reduction of one synthetic step and a greater than 30% improvement in yield over the known method.

Synthesis and evaluation of imidazole-4,5- and pyrazine-2,3-dicarboxamides targeting dengue and yellow fever virus

“…The general procedure employed for the synthesis of dissymmetrically disubstituted I45DCs is shown in Scheme 1 . Imidazole-4,5-dicarboxylic acid 10 was allowed to reflux with SOCl 2 in toluene with catalytic DMF to afford pyrazinedione diacid dichloride 11 in 92% yield [20] . The literature route for amide formation suggests hydrolysis of the acid chlorides to carboxylic acids by the addition of water.…”

“…Amines are then added to open both acyl imidazole bonds affording two identical imidazole analogs. Baures et al., replaced the water with phenol, thereby modulating the reactivity of the acid chloride in comparison with an acyl imidazole bond for the subsequent addition of two different amines [20] . The difficulty in preparing such analogs is that their synthesis is highly dependent upon the substituents to be introduced.…”

Developing imidazoles as CEST MRI pH sensors

“…1H-1,2,3-Triazole-4,5-dicarbonyl dichloride (16) was prepared using the same procedure as for 15 (67). 16 326 mg (1.7 mmol) and THF 10 mL were added to a dry flask.…”

Scaffolds for Blocking Protein-Protein Interactions

“…Helix D of the CD81 protein was determined to be essential for HCV-E2 binding via crystal structure analysis and was, thus, targeted for this study. The bisimidazole scaffolds, derived from N,N'-disubstituted imidazole-4,5-dicarboxamides, are well suited as -helix mimetics due to the fact that these molecules are relatively simple to prepare, amphiphilic, and have known stable conformations [47]. The intramolecular hydrogen bond stabilizes the amide group substituents in a conformation which closely matches the side chain separations on one face of an -helix, Fig.…”