1,2,4-Triazolo[1,5-a]quinoxaline as a Versatile Tool for the Design of Selective Human A₃ Adenosine Receptor Antagonists:  Synthesis, Biological Evaluation, and Molecular Modeling Studies of 2-(Hetero)aryl- and 2-Carboxy-Substitued Derivatives

Abstract

A number of 4-oxo-substituted 1,2,4-triazolo[1,5-a]quinoxaline derivatives bearing at position-2 the claimed (hetero)aryl moiety (compounds 1-15) but also a carboxylate group (16-28, 32-36) or a hydrogen atom (29-31) were designed as human A3 (hA3) adenosine receptor (AR) antagonists. This study produced some interesting compounds and among them the 2-(4-methoxyphenyl)-1,2,4-triazolo[1,5-a]quinoxalin-4-one (8), which can be considered one of the most potent and selective hA3 adenosine receptor antagonists reported till now. Moreover, as a new finding, replacement of the classical 2-(hetero)aryl moiety with a 2-carboxylate function (compounds 16-28 and 32-36) maintained good hA3 AR binding activity but, most importantly and interestingly, produced a large increase in hA3 versus hA1 selectivity. A receptor-based SAR analysis provided new interesting insights about the steric and electrostatic requirements that are important for the anchoring of these derivatives at the hA3 receptor recognition site, thus highlighting the versatility of the triazoloquinoxaline scaffold for obtaining potent and selective hA3 AR antagonists.

A New Series of 2-Alkoxy(aralkoxy)-[1,2,4]triazolo[1,5-a]quinazolin-5-ones as Adenosine Receptor Antagonists

“…1) those containing a 1,2,4-triazoloquinoxaline scaffold have been extensively explored, showing to be an extremely versatile motif during the identification of new valuable and selective AR ligands. [23][24][25][26][27][28][29][30][31][32][33] In our previous papers, [34][35][36] we have described the synthetic methodology to obtain a new series of 2-alkoxy-[1,2,4]triazolo[1,5-a]quinazolin-5-ones and their derivatives 1-11, Chart 1. In this scenario, and as a part of our interest in the search for novel adenosine receptor antagonists, we herein report the pharmacological characterization of our compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) at all adenosine receptor subtypes.…”

1,2,4-Triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A3 receptor antagonists. Synthesis, structure–affinity relationships and molecular modeling studies

“…9 The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) ring system is a recurrent structural core which has been used to obtain tricyclic AR antagonists. [15][16][17][18] The first AR antagonists belonging to this series were designed as structural analogues of CGS15943 (9-chloro-2-(2-furanyl) [1,2,4]triazolo [1,5-c]quinazolin-5-amine) 19 in the midnineties 15 and, since then, many other TQX derivatives of interest have been developed by our research group. In particular, the 8-chloro-2-phenyl-1,2,4-triazolo[1,5-a]quinoxalin-4-amine 17 (1A, Fig.…”

“…This study produced some interesting compounds endowed with good hA 3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA 3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds [16][17][18][19][20][21][22][23]. These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA 3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a K i value in the micro-molar range and high hA 3 selectivity versus both hA 1 and hA 2A AR subtypes.…”

Synthesis of Novel Triazolo[4,3-<i>a</i>]Quinoxaline Darivatives Containing Pyridinyl and Thiazole Nucleous

“…A double site-and regio-selective 1,3-dipolar cycloaddition of arylnitrilimines to quinoxalines gave bis-1,2,4-triazolo[4,3-a:3',4'-c]quinoxalines [16]. N'-(5-methyl-2 nitrophenyl)benzohydrazide reacted with ethyl (chlorocarbonyl)formate to give triazolo quinoxalines [17]. The solvent free reaction of 3-methylquinoxalin-2-ylhydrazones and iodobenzene diacetate afforded triazolo quinoxalines with good yield [18].…”