SAR analysis of a series of acylthiourea derivatives possessing broad-spectrum antiviral activity |
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Authors: | Burgeson James R Moore Amy L Boutilier Jordan K Cerruti Natasha R Gharaibeh Dima N Lovejoy Candace E Amberg Sean M Hruby Dennis E Tyavanagimatt Shanthakumar R Allen Robert D Dai Dongcheng |
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Institution: | SIGA Technologies, Inc., 4575 SW Research Way, Suite 230, Corvallis, OR 97333, United States. |
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Abstract: | 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 (EC(50)=0.25 μM) and La Crosse virus (EC(50)=0.27 μM) 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). |
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