Asymmetric synthesis of host-directed inhibitors of myxoviruses

作者：Moore Terry W; Sana Kasinath; Yan Dan; Thepchatri Pahk; Ndungu John M; Saindane Manohar T; Lockwood Mark A; Natchus Michael G; Liotta Dennis C; Plemper Richard K; Snyder James P; Sun Aiming^*

来源：Beilstein Journal of Organic Chemistry, 2013, 9: 197-203.

DOI：10.3762/bjoc.9.23

• asymmetric synthesis
• benzimidazole
• host-directed
• myxovirus
• small molecule inhibitor

High-throughput screening (HTS) previously identified benzimidazole 1 (JMN3-003) as a compound with broad antiviral activity against different influenza viruses and paramyxovirus strains. In pursuit of a lead compound from this series for development, we sought to increase both the potency and the aqueous solubility of 1. Lead optimization has achieved compounds with potent antiviral activity against a panel of myxovirus family members (EC50 values in the low nanomolar range) and much improved aqueous solubilities relative to that of 1. Additionally, we have devised a robust synthetic strategy for preparing 1 and congeners in an enantio-enriched fashion, which has allowed us to demonstrate that the (S)-enantiomers are generally 7- to 110-fold more potent than the corresponding (R)-isomers.

• 出版日期2013-1-30