Synthesis and antiviral activity of 2‐substituted 4‐aminoquinoline and its analogous derivatives

Herein we describe an efficient Lewis acid-mediated one-pot synthesis of 2-substituted 4-aminoquinolines from commercially available anthranilonitriles and substituted acetophenones via a Friedlander type annulation reaction. The protocol avoids any transition metal catalysts, has a wide substrate scope, and exclusively produces 4-aminoquinolines in excellent yields. Screening of all the new compounds for in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells revealed nine analogues with good virus-inhibiting activity and a favorable toxicity profile. Among them, two compounds, 3a (IC50: 1.7 mu M, SI = 30) and 3l (IC50: 4.0 mu M, SI = 25) with higher potency are the best anti-influenza hit analogues for further structural optimization.