SAR analysis of a series of acylthiourea derivatives possessing broad-spectrum antiviral activity

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• 作者：James R. Burgeson ; Amy L. Moore ; Jordan K. Boutilier ; Natasha R. Cerruti ; Dima N. Gharaibeh ; Candace E. Lovejoy ; Sean M. Amberg ; Dennis E. Hruby ; Shanthakumar R. Tyavanagimatt ; Robert D. Allen III ; Dongcheng Dai ; ^{ddai@siga.com}
• 关键词：HUPJQYGQLLLQOB-UHFFFAOYSA-N ; CWDLOTUBJXUNBU-UHFFFAOYSA-N ; BZPFKVOMVNJHDK-UHFFFAOYSA-N
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 July, 2012
• 卷：22
• 期：13
• 页码：4263-4272
• 文件大小：3320 K

摘要

A series of acylthiourea derivatives were designed, synthesized, and evaluated for broad-spectrum antiviral activity with selected viruses from Poxviridae (vaccinia virus) and two different genera of the family Bunyaviridae (Rift Valley fever and La Crosse viruses). A compound selected from a library screen, compound 1, displayed submicromolar antiviral activity against both vaccinia virus (EC₅₀ = 0.25 渭M) and La Crosse virus (EC₅₀ = 0.27 渭M) in cytopathic effect (CPE) assays. SAR analysis was performed to further improve antiviral potency and to optimize drug-like properties of the initial hits. During our analysis, we identified 26, which was found to be nearly fourfold more potent than 1 against both vaccinia and La Crosse viruses. Selected compounds were further tested to more fully characterize the spectrum of antiviral activity. Many of these possessed single digit micromolar and sub-micromolar antiviral activity against a diverse array of targets, including influenza virus (Orthomyxoviridae), Tacaribe virus (Arenaviridae), and dengue virus (Flaviviridae).