标题：Design, synthesis and biological evaluation of novel acetamide-substituted doravirine and its prodrugs as potent HIV-1 NNRTIs
作者：Wang, Zhao; Yu, Zhao; Kang, Dongwei; Zhang, Jian; Tian, Ye; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng; L 更多 作者机构：[Wang, Zhao; Yu, Zhao; Kang, Dongwei; Zhang, Jian; Tian, Ye; Zhan, Peng; Liu, Xinyong] Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,K 更多
通讯作者：Kang, DW;Zhan, P;Liu, XY
通讯作者地址：[Kang, DW; Zhan, P; Liu, XY]Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandon 更多
来源：BIOORGANIC & MEDICINAL CHEMISTRY
关键词：HIV-1; NNRTIs; Doravirine; Acetamide; Prodrug; Drug design
摘要：A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8 nM. Among them, the two most potent compounds 8i (EC50 = 59.5 nM) and 8k (EC50 = 54.8 nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50= 12.8 mu M) and comparable to doravirine (EC50= 13 nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N + Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail.