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Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-04-09 , DOI: 10.1021/acs.jmedchem.0c02183 S Kaleem Ahmed 1 , Nicole N Haese 2 , Jaden T Cowan 1 , Vibha Pathak 1 , Omar Moukha-Chafiq 1 , Valerie J Smith 1 , Kevin J Rodzinak 1 , Fahim Ahmad 1 , Sixue Zhang 1 , Kiley M Bonin 2 , Aaron D Streblow 2 , Cassilyn E Streblow 2 , Craig N Kreklywich 2 , Clayton Morrison 3 , Sanjay Sarkar 3 , Nathaniel Moorman 4 , Wes Sander 4 , Robbie Allen 5 , Victor DeFilippis 2 , Babu L Tekwani 1 , Mousheng Wu 1 , Alec J Hirsch 2 , Jessica L Smith 2 , Nichole A Tower 1 , Lynn Rasmussen 1 , Robert Bostwick 1 , Joseph A Maddry 1 , Subramaniam Ananthan 1 , John M Gerdes 1 , Corinne E Augelli-Szafran 1 , Mark J Suto 1 , Thomas E Morrison 6 , Mark T Heise 3 , Daniel N Streblow 2 , Ashish K Pathak 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-04-09 , DOI: 10.1021/acs.jmedchem.0c02183 S Kaleem Ahmed 1 , Nicole N Haese 2 , Jaden T Cowan 1 , Vibha Pathak 1 , Omar Moukha-Chafiq 1 , Valerie J Smith 1 , Kevin J Rodzinak 1 , Fahim Ahmad 1 , Sixue Zhang 1 , Kiley M Bonin 2 , Aaron D Streblow 2 , Cassilyn E Streblow 2 , Craig N Kreklywich 2 , Clayton Morrison 3 , Sanjay Sarkar 3 , Nathaniel Moorman 4 , Wes Sander 4 , Robbie Allen 5 , Victor DeFilippis 2 , Babu L Tekwani 1 , Mousheng Wu 1 , Alec J Hirsch 2 , Jessica L Smith 2 , Nichole A Tower 1 , Lynn Rasmussen 1 , Robert Bostwick 1 , Joseph A Maddry 1 , Subramaniam Ananthan 1 , John M Gerdes 1 , Corinne E Augelli-Szafran 1 , Mark J Suto 1 , Thomas E Morrison 6 , Mark T Heise 3 , Daniel N Streblow 2 , Ashish K Pathak 1
Affiliation
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A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC50 = 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC90 = 270 nM and VTR of 4.5 log at 10 μM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway.
中文翻译：
苯并环烯抑制剂靶向基孔肯雅病毒复制
苯并[6]环烯，4-(叔丁基) -N- (3-甲氧基-5,6,7,8-四氢萘-2-基)苯甲酰胺( 1a )被鉴定为基孔肯雅病毒的抑制剂( CHIKV) 具有抗病毒活性 EC 90 = 1.45 μM，10 μM 时病毒滴度降低 (VTR) 为 2.5 log，在正常人真皮成纤维细胞中未观察到细胞毒性 (CC 50 = 169 μM)。为提高1a的效力、功效和类药特性而进行的化学努力产生了一种新型先导化合物8q，它具有出色的细胞抗病毒活性（EC 90 = 270 nM，10 μM 时的 VTR 为 4.5 log）并改善了肝微粒体稳定性。CHIKV 电阻模拟1a，化合物1c，追踪到 nsP3 宏结构域中的突变。进一步的作用机制研究表明，除 CHIKV nsP3 宏结构域外，化合物还通过抑制人二氢乳清酸脱氢酶发挥作用。在化合物8q的体内CHIKV 攻击小鼠模型中观察到中等功效，因为病毒复制从嘧啶补救途径中拯救出来。
更新日期：2021-04-22
中文翻译：
苯并环烯抑制剂靶向基孔肯雅病毒复制
苯并[6]环烯，4-(叔丁基) -N- (3-甲氧基-5,6,7,8-四氢萘-2-基)苯甲酰胺( 1a )被鉴定为基孔肯雅病毒的抑制剂( CHIKV) 具有抗病毒活性 EC 90 = 1.45 μM，10 μM 时病毒滴度降低 (VTR) 为 2.5 log，在正常人真皮成纤维细胞中未观察到细胞毒性 (CC 50 = 169 μM)。为提高1a的效力、功效和类药特性而进行的化学努力产生了一种新型先导化合物8q，它具有出色的细胞抗病毒活性（EC 90 = 270 nM，10 μM 时的 VTR 为 4.5 log）并改善了肝微粒体稳定性。CHIKV 电阻模拟1a，化合物1c，追踪到 nsP3 宏结构域中的突变。进一步的作用机制研究表明，除 CHIKV nsP3 宏结构域外，化合物还通过抑制人二氢乳清酸脱氢酶发挥作用。在化合物8q的体内CHIKV 攻击小鼠模型中观察到中等功效，因为病毒复制从嘧啶补救途径中拯救出来。
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