Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Main Authors: Terry W. Moore, Kasinath Sana, Dan Yan, Pahk Thepchatri, John M. Ndungu, Manohar T. Saindane, Mark A. Lockwood, Michael G. Natchus, Dennis C. Liotta, Richard K. Plemper, James P. Snyder, Aiming Sun
• Format: Article
• Language: English
• Published: Beilstein-Institut 2013-01-01
• Series: Beilstein Journal of Organic Chemistry
• Subjects: asymmetric synthesis; benzimidazole; host-directed; myxovirus; small molecule inhibitor
• Online Access: https://doi.org/10.3762/bjoc.9.23

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.