Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIV‑1 and EV-A71 Entry Inhibitors

We have recently described a new generation of potent human immunodeficiency virus (HIV) and EV-A71 entry inhibitors. The prototypes contain three or four tryptophan (Trp) residues bearing an isophthalic acid moiety at the C2 position of each side-chain indole ring. This work is now extended by both shifting the position of the isophthalic acid to C7 and synthesizing doubly arylated C2/C7 derivatives. The most potent derivative (50% effective concentration (EC50) HIV-1, 6 nM; EC50 EV-A71, 40 nM), 33 (AL-518), is a C2/C7 doubly arylated tetrapodal compound. Its superior anti-HIV potency with respect to the previous C2-arylated prototype is in consonance with its higher affinity for the viral gp120. 33 (AL-518) showed comparable antiviral activities against X4 and R5 HIV-1 strains and seems to interact with the tip and base of the gp120 V3 loop. Taken together, these findings support the interest in 33 (AL-518) as a useful new prototype for anti-HIV/EV71 drug development.本团队此前已报道了一类新型强效人类免疫缺陷病毒（HIV）与肠道病毒71型（EV-A71）进入抑制剂。其先导化合物含有3或4个色氨酸（Trp）残基，每个残基的侧链吲哚环C2位均连有间苯二甲酸基团。本研究在此基础上，将间苯二甲酸的连接位点迁移至C7位，并合成了C2/C7双芳基化衍生物。活性最优的衍生物为化合物33（AL-518），一种C2/C7双芳基化四臂化合物，其针对HIV-1的半数有效浓度（EC50）为6 nM，针对EV-A71的EC50为40 nM。相较于此前报道的C2芳基化先导化合物，该化合物的抗HIV活性更优，这与其对病毒gp120蛋白具有更高亲和力的结果一致。化合物33（AL-518）对X4型与R5型HIV-1毒株均展现出相当的抗病毒活性，且推测其可与gp120的V3环顶端及基部区域相互作用。综上，本研究结果证实化合物33（AL-518）是一款极具开发潜力的抗HIV/EV-A71新药先导化合物。