Scouting Human A₃ Adenosine Receptor Antagonist Binding Mode Using a Molecular Simplification Approach: From Triazoloquinoxaline to a Pyrimidine Skeleton as a Key Study

Abstract

The concept of molecular simplification as a drug design strategy to shorten synthetic routes, while keeping or enhancing the biological activity of the lead drug, has been applied to design new classes of human A3 adenosine receptor (AR) antagonists. Over the past decade, we have focused a part of our research on the study of AR antagonists belonging to strictly correlated classes of tricyclic compounds. One of these classes is represented by the 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, either 4-amino or 4-oxo-substituted, which were intensively investigated by evaluating the effect of different substituents on the 2-phenyl ring and on the 4-amino group. Using an in silico molecular simplification approach, a new series of easily synthesizable 2-amino/2-oxoquinazoline-4-carboxamido derivatives have been discovered, presenting high affinity and selectivity against human A3 AR.

The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A3 Adenosine Receptor Antagonists

“…Moreover, docking simulations were also performed on compound B, a quinazoline-4-carboxamide derivative (QZ series) previously reported. 28 Therefore, all of the selected compounds were docked into the TM binding site of the hA 3 AR three-dimensional model, to identify their hypothetical binding modes at this receptor and to analyze possible analogies among the different series. In addition, docking simulations at the hA 2A AR were carried out to explain the hA 3 versus hA 2A selectivity profile of all of these derivatives.…”

“…The planarity of the QZ derivative, due to this intramolecular H-bond, seems to increase complementarity with the hA 3 receptor; the key role of this intramolecular H-bond was already analyzed in previous docking studies of the QZ derivatives carried out on the rhodopsin-based homology model of hA 3 AR. 28 The hypothetical binding mode, at the hA 3 AR, of one of the herein reported 2-phenyl-phthalazin-1(2H)-ones (compound 9, hA 3 AR K i = 178.4 nM) is displayed in Figure 2C. Molecular docking simulations show that the new compound 9 is efficiently accommodated into the TM binding cavity with the 4-phenylureido substituent directed toward the extracellular loop region.…”

Insights into the N,N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: an alternative N-monoacylation reaction

“…Previous reports related to this type of transformations have appeared in the literature, but they have been only briefly investigated. 6,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Activation methods have found the reagents to be resistant to amide formation of 2-aminopyrimidines with low or moderate yields. [11][12][13][14] By the addition of the appropriate benzoyl chloride to 2-amino-4-(3-pyridinyl)pyrimidine in refluxing pyridine, 6 a group of N-mono-and N,N-dibenzoyl derivatives has been prepared in low yield.…”

“…6,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Activation methods have found the reagents to be resistant to amide formation of 2-aminopyrimidines with low or moderate yields. [11][12][13][14] By the addition of the appropriate benzoyl chloride to 2-amino-4-(3-pyridinyl)pyrimidine in refluxing pyridine, 6 a group of N-mono-and N,N-dibenzoyl derivatives has been prepared in low yield. The same mixture of N-monobenzoyland N,N-dibenzoyl-2-aminopyrimidines has been obtained (15% and 45%, respectively) by reaction of the 2-aminopyrimidine scaffold with benzoyl chloride in refluxing dichloromethane 15 and excess pyridine for 48 h. Peracylation of a 2,4-diaminopyrimidine-derivative has also been obtained with excess of benzoyl chloride in pyridine at room temperature for 18 hours, 16,17 while N,N-dibenzoyl-deoxycytidine has been formed as a by-product in the N-benzoylation of deoxycytidine 18 and 2-aminopyridines.…”

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

“…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. 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 hA 3 AR antagonists (compounds [24][25][26][27]. These derivatives, though lacking the classical structural requirements for the anchoring at the hA 3 receptor site, show high hA 3 affinity and in some case selectivity versus hA 1 and hA 2A subtypes.…”