Inhibitors of Adenosine Deaminase: Continued Studies of Structure‐Activity Relationships in Analogues of Coformycin

Abstract

Synthesis and adenosine deaminase (ADA) inhibitory activity of two analogues of coformycin, containing the imidazo[4,5-e][1,2,4]triazepine ring system, have been reported as part of the structure-activity relationship (SAR) studies to explore the factors responsible for the extremely tight-binding characteristics of coformycins to ADA.

Synthesis of Pyrazolylthiazole and Pyrazolyl-1,2,4-Triazepine Derivatives

“…The signals centred at 141.40 and 140.05 ppm in the 13 C NMR spectra, assigned to C=N functions, confer further support to the structure assigned to 4a. Furthermore, the downfield shift of the pyrazole-NH clearly shows the presence of intramolecular H-bonding as in structure 4a.…”

“…The method of Vogeli et al 21 based on analysis of the (J C-H ) coupling constants between H-2 and endocyclic (C-1) or exocyclic ester carbonyl carbon atoms, was used to establish the size of the ring formed. In the 1 H-coupled 13 C-spectrum, the magnitude of the coupling between C-1 and H-2 (J = 5.6 Hz) requires a three-and not a two-bond coupling, 2,21 thus excluding structure 6. Also, this value indicates a (Z) configuration of the exocyclic double bond in compounds 3a and 3b which corresponds to the trans addition of the SH group to the triple bond in DMAD 2 (Scheme 2).…”

“…11 Interest in azepine-containing bicyclic rings has resulted from finding immunosuppressant and antitumour activity for such natural products as coformicine 12 and pentostatin 12 and their synthetic analogues. 13 Motivated by these findings coupled with our investigations in the field of pyrazoles 9 and other heterocyclic compounds, [14][15][16][17] in the present work, we studied the reactions of N-(3-substituted-1H-pyrazol-5-yl)hydrazinecarbothioamides 1a,b with dimethyl acetylenedi-carboxylate 2 and developed methods for the synthesis of new derivatives of pyrazolylthiazolone and pyrazolyltriazepine.…”

Investigations into the Origin of the Molecular Recognition of Several Adenosine Deaminase Inhibitors

“…2-(Benzylthio)pyrimidine-4,6-diamine (35). A suspension of 4,6-diaminopyrimidine-2-thiol, 34 76 (4 g, 26.45 mmol in 120 mL MeOH), was dissolved in 0.25 M NaOH (111 mL) and stirred at RT for 1 h. The solvent was evaporated under high vacuum.…”

Reaction of acetylenedicarboxylic acids esters with 4,5-dihydro-1H-pyrazole-1-carbothioamides and 3,4,5,6-tetrahydro-2H-1,2,4-triazepine-3-thiones

“…Recently, pyrazolinecarbothioamides have been attracting increasing attention since some of these compounds display hypotensive [2], antidepressant [3], and anti-inflammatory activity [4], serve as inhibitors of cholinesterase [6][7][8], monoamine oxidase A [3], and monoamine oxidase B [3,5], and have antiamebic action [6][7][8]. Interest in bicyclic compounds containing azepine rings has arisen upon finding immunosuppressant and antitumor activity for such natural products as coformicine [12][13][14][15] and pentostatin [12][13][14][15] and their synthetic analogs [16][17][18][19]. Thus, there is current interest in the synthesis of new derivatives of pyrazoline and azepines.…”