title: Development of (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336: Novel 2-amidinophenylbenzamides as potent inhibitors of venezuelan equine encephalitis virus.
abstract: Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC50 = 0.8 μM), limited cytotoxic liability (CC50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC50 = 0.02-0.04 μM, CC50 > 50 μM) while limiting in vitro viral replication (EC90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg(-1) day(-1) and viral replication appeared to be inhibited through interference of viral nonstructural proteins.
authors.affiliation: University of Kansas Specialized Chemistry Center , Lawrence, Kansas 66049, United States.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Schroeder
authors.forename: Tuanli
authors.initials: T
authors.lastname: Yao
authors.forename: Julie
authors.initials: J
authors.lastname: Sotsky
authors.forename: Robert A
authors.initials: RA
authors.lastname: Smith
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Roy
authors.forename: Yong-Kyu
authors.initials: YK
authors.lastname: Chu
authors.forename: Haixun
authors.initials: H
authors.lastname: Guo
authors.forename: Nichole A
authors.initials: NA
authors.lastname: Tower
authors.forename: James W
authors.initials: JW
authors.lastname: Noah
authors.forename: Sara
authors.initials: S
authors.lastname: McKellip
authors.forename: Melinda
authors.initials: M
authors.lastname: Sosa
authors.forename: Lynn
authors.initials: L
authors.lastname: Rasmussen
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.forename: E Lucile
authors.initials: EL
authors.lastname: White
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.forename: Colleen B
authors.initials: CB
authors.lastname: Jonsson
authors.forename: Donghoon
authors.initials: D
authors.lastname: Chung
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004666:Encephalitis Virus, Venezuelan Equine / Q000187:drug effects*; D004685:Encephalomyelitis, Venezuelan Equine / Q000188:drug therapy; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000597475:2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide; D000998:Antiviral Agents; D001549:Benzamides; D006574:Heterocyclic Compounds, 2-Ring; D010879:Piperazines; D052999:Quinazolinones; D054852:Small Molecule Libraries