Synthesis of 2-arylfuro[3,2-b]pyridines: Effect of the C2-aryl group on melatoninergic activity

•Original route to 2-arylfuro[3,2-b]pyridines allowing large molecular diversity.•New furo[3,2-b]pyridine ligands with good melatoninergic activity.•Influence of C2-aryl groups on the affinity and activity on MT1 and MT2 receptors.

We report herein an efficient synthesis of 2-substituted furo[3,2-b]pyridines and their biological evaluation as melatonin receptors ligands. The proposed eight-step sequence ending with a Suzuki coupling allowed a rapid access to various analogues. The steric hindrance and the conformation of the aryl group in C2-position were evaluated regarding the selectivity of the molecule for one of the two high affinity melatonin receptors as well as the activity profile of the compound. Introduction of 1-naphthyl substituent gave the best result in terms of selectivity with a MT1/MT2 ratio of about 150 (MT1 Ki = 198 nM, MT2 Ki = 1.3 nM).

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