Discovery of chiral N-2′-aryletheryl-1′-alkoxy-ethyl substituted arylisoquinolones with anti-inflammatory activity from the nucleophilic addition reactions of the thiophenols and oxazolinium

Herein we disclosed the novel nucleophilic addition reactions of the thiophenols and oxazolinium (DCZ0358) to produce N-2′-aryletheryl-1′-alkoxy-ethyl substituted arylisoquinolones. After evaluating the anti-inflammatory activity in vitro, 2d was found having significant anti-TNFα activity. Through the amplified synthesis of 2d, four monomers (3a-b and 4a-d) were obtained by chiral separation of the product. The reaction mechanism was proposed and explored by the control experiments. However, only the R-stereoisomers 3b and 4b have significant anti-TNFα activity in vitro (IC50 = 56 and 14 nM, respectively). Moreover, 4b exerts potent therapeutic effects on ulcerative colitis in vivo (30 mg/kg bw, qd, i. g.). The subsequent bio-target exploration of compound 4b via molecular docking and the experimental validation disclosed that 4b has 3-fold selectivity of binding activity on estrogen receptor (ER) beta (β) (Ki = 760.86 nM) vs. alpha (α) (Ki = 2320.58 nM). Thus, it provides a novel type of non-steroidal leads for developing anti-inflammatory drugs.