SAR analysis of a series of acylthiourea derivatives possessing broad-spectrum antiviral activity.
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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James R
JR
Burgeson
Amy L
AL
Moore
Jordan K
JK
Boutilier
Natasha R
NR
Cerruti
Dima N
DN
Gharaibeh
Candace E
CE
Lovejoy
Sean M
SM
Amberg
Dennis E
DE
Hruby
Shanthakumar R
SR
Tyavanagimatt
Robert D
RD
Allen
Dongcheng
D
Dai
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018050:Arenavirus / Q000187:drug effects; D003716:Dengue Virus / Q000187:drug effects; D018062:La Crosse virus / Q000187:drug effects; D009975:Orthomyxoviridae / Q000187:drug effects; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014616:Vaccinia virus / Q000187:drug effects
D000998:Antiviral Agents; D013890:Thiourea