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.
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.
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DOI：
10.1021/jm501203v
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发表时间：
2014-10-23
影响因子：
7.3
通讯作者：
Golden JE
中科院分区：
文献类型：
--
作者：
Schroeder CE;Yao T;Sotsky J;Smith RA;Roy S;Chu YK;Guo H;Tower NA;Noah JW;McKellip S;Sosa M;Rasmussen L;Smith LH;White EL;Aubé J;Jonsson CB;Chung D;Golden JE
委内瑞拉马脑炎病毒(VEEV)是一种新出现的致病性甲型病毒，可导致人类重大疾病。鉴于现有治疗方案的缺乏和VEEV作为武器制剂的重要性，围绕具有良好的细胞抗病毒活性(EC_(50)=0.8μM)、有限的细胞毒性(CC50>；50μM)和适度的体外减少病毒后代的效果(5μM时是63倍)的喹唑烷酮筛选HIT-1，启动了一项优化工作。支架优化揭示了一种新的重排提供酰胺，特别是化合物45，它被发现在低纳摩尔范围内有效地抑制几个VEEV毒株而没有细胞毒性(EC50=0.02-0.04μM，CC50>；50μM)，同时限制体外病毒复制(EC90=0.17μM)。观察了45岁的小鼠的脑暴露情况。剂量为5 mg·kg~(-1)·d~(-1)对VEEV感染的小鼠有明显的保护作用，病毒复制似乎受到病毒非结构蛋白的干扰。
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.
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理解Kaplan-Meier曲线的实用指南。
影响因子：
3.4
作者：
Rich, Jason T.;Neely, J. Gail;Paniello, Randal C.;Voelker, Courtney C. J.;Nussenbaum, Brian;Wang, Eric W.
通讯作者：
Wang, Eric W.
影响因子：
3.7
作者：
Kehn-Hall K;Narayanan A;Lundberg L;Sampey G;Pinkham C;Guendel I;Van Duyne R;Senina S;Schultz KL;Stavale E;Aman MJ;Bailey C;Kashanchi F
通讯作者：
Kashanchi F
影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian
DOI：
10.1128/aem.27.1.150-153.1974
发表时间：
1974-01-01
期刊：
APPLIED MICROBIOLOGY
影响因子：
--
作者：
COLE, FE;MAY, SW;EDDY, GA
通讯作者：
EDDY, GA
影响因子：
3.7
作者：
DAVIS, NL;BROWN, KW;JOHNSTON, RE
通讯作者：
JOHNSTON, RE