Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A1 and A2A Receptors, and Efficacy in Animal Models of Depression

Abstract

New compounds with a 7-amino-2-arylmethyl-thiazolo[5,4-d]pyrimidine structure were synthesized and evaluated in vitro for their affinity and/or potency at the human (h) A1, hA2A, hA2B, and hA3 adenosine receptors (ARs). Several compounds (5, 8–10, 13, 18, 19) were characterized by nanomolar and subnanomolar binding affinities for the hA1 and the hA2A AR, respectively. Results of molecular docking studies supported the in vitro results. The 2-(2-fluorobenzyl)-5-(furan-2yl)-thiazolo[5,4-d]pyrimidin-7-amine derivative 18 (hA1 Ki = 1.9 nM; hA2A Ki = 0.06 nM) was evaluated for its antidepressant-like activity in in vivo studies, the forced swimming test (FST), the tail suspension test (TST), and the sucrose preference test (SPT) in mice, showing an effect comparable to that of the reference amitriptyline.

Design, synthesis and biological activities of 1,2,4‐triazolo[1,5‐a]pyrimidine‐7‐amine derivatives bearing 1,2,4‐oxadiazole motif

“…[1][2][3] Among them, pyrimidine is a common nitrogen-linked heterocycle, which exist in natural products or synthetic compounds. They possessed diverse bioactivity, such as adenosine receptors, [4] antimicrobial, [5] anti-tumor, [6] K-Ca channel blockers, [7] anti-HIV, [8] insecticidal, [9] and fungicidal activities. [10] Some of pyrimidinamine compounds had been commercialized as pesticides, such as the fungicides Ethirimol and Bupirimate, the insecticide Dicyclanil, and the herbicide Nicosulfuron.…”