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

Abstract

The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16-23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA3 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 Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24-27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.

Synthesis, Characterization, Biological and Photoluminescence Study of Co(II) Complexes of Fused Heterocyclic Ring Systems

“…The other stretching frequencies like >C=N (pyrimidine), C=S, appears at 1530 and 1393 cm -1 for the ligand and 1528 and 1390 cm -1 in the complex and the appearance of these bands at same region without considerable shift in the complexes show the non-involvement of these groups in co-ordination. [4][5][6] The stretching frequencies of the ligand and the complexes are shown in Table SI 1a and the FT-IR spectra of the ligand and the complexes (1-6) are shown in Supplementary Information (SI) Figure SI. 2a to 2f respectively.…”

Novel human adenosine receptor antagonists based on the 7-amino-thiazolo[5,4-d]pyrimidine scaffold. Structural investigations at the 2-, 5- and 7-positions to enhance affinity and tune selectivity

“…In continuation of our studies directed towards the identification of new AR antagonists [23][24][25][26][27][28], in a recent paper we disclosed the 5-methyl-2-phenylthiazolo [5,4-d]pyrimidin-7-one 1 [29] which proved to be a potent and selective human (h) A 3 AR antagonist, being inactive at the other AR subtypes (Fig. 1).…”

1,3-Dipolar cycloaddition of cyanopyridines to heterocyclic N-imines – combined experimental and theoretical studies

“…Similarly, [1,2,4]triazolo [1,5-a]pyrimidines, which chemistry recently was reviewed, have a broad spectrum of biological activity [9]. [1,2,4]Triazolo [1,5a]pyrazines and quinoxalines was used in design of A2A [10,11] and A3 [12,13] The practical significance of such scaffolds stimulated the development of viable synthetic methods for their preparation [9,14]. One of the common approaches to [1,2,4]triazolo [1,5-a]azines is an oxidative cyclization of 2-pyridyl, pyrazinyl, pyrimidyl etc., amidines or aminoguanidines to form N-N bond with various oxidants such as Pb(OAc)4 [15], PhI(OCOCF3)2 [16], iodine [17], N-Cl reagents [18,19] or electrolysis [20].…”