Inhibition of Adenosine Deaminase by Novel 5:7 Fused Heterocycles Containing the Imidazo[4,5-e][1,2,4]triazepine Ring System:  A Structure−Activity Relationship Study

Abstract

As part of a program to explore structure-activity relationships for the extremely tight binding inhibition characteristics of coformycins to adenosine deaminase, a series of analogues (1a-1h) containing the imidazo[4,5-e][1,2,4]triazepine ring system has been synthesized and screened in vitro against a mammalian adenosine deaminase for inhibitory activity. While compounds 1a and 1b were synthesized in five steps starting from 4-nitroimidazole, others were derived from 1a through simple exchange reactions with the appropriate alcohols. The observed kinetics profiles and K(i) values suggest that the target compounds are competitive inhibitors that bind 6-9 orders of magnitude less tightly to the enzyme. Compounds 1c and 1d were the most active in the series with K(i)'s ranging from 12 to 15 microM.

Targeting Metalloenzymes for Therapeutic Intervention

“…872 Eight derivatives were synthesized with several changes, including: a lack of sugar moiety, which weakens the binding interaction by removing stabilizing hydrogen bonds; inclusion of alkyl groups at position 1; an additional nitrogen atom at position 7 to reduce nucleophilicity of the hydroxyl at position 8; and, addition of methyl group at position 6 and 7 to avoid rearrangement of the ring system. 872 Compound ADAi-2 ( K i = 12 μM) in this series was the most active (Figure 91). Overall, these inhibitors have inhibition constants many orders of magnitude worse than pentostatin.…”

“…Overall, these inhibitors have inhibition constants many orders of magnitude worse than pentostatin. 872 Their poorer activity is attributed to the lack of a sugar moiety, which forms several hydrogen bonds to protein residues. No structural data has been reported for these inhibitors, so it is unclear how these inhibitors bind to ADA and if the active site adopts closed or open conformation.…”

Copper-catalyzed three-component synthesis of 5-acetamidoimidazoles from carbodiimides, acyl chlorides and isocyanides

“…1). 7 Obviously, substituted 5-aminoimidazoles are also useful intermediates in the synthesis of purine, 8 and the purine-derived natural products. For example, heteromine A (6a) and B (6b), 9 cytotoxic against several cancer cell lines, have been synthesized from 5-amino-4-cyanoimidazole.…”

Synthesis and antimicrobial activity of chromone-linked 2-pyridone fused with 1,2,4-triazoles, 1,2,4-triazines and 1,2,4-triazepines ring systems

“…14 On the other hand, 1,2,4-triazoles, 1,2,4-triazines and 1,2,4-triazepines have been found to possess a wide spectrum of pharmacological, medicinal and biological activities. [15][16][17][18][19][20] As part of our research work aiming to the synthesis of a variety of fused heterocyclic systems for biological evaluation, we report here efficient and convenient synthetic methods of different biodynamic nitrogen heterocycles such as 1,2,4-triazoles, 1,2,4-triazines and 1,2,4-triazepines fused with 2-pyridone ring containing a chromone moiety.…”