Scouting human A3 adenosine receptor antagonist binding mode using a molecular simplification approach: from triazoloquinoxaline to a pyrimidine skeleton as a key study.

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 A 3 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 A 3 AR.