Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)  

作　　者：Sameera Senaweera Tiffany C.Edwards Jayakanth Kankanala Yan Wang Rajkumar Lalji Sahani Jiashu Xie Robert J.Geraghty Zhengqiang Wang 

机构地区：[1]Center for Drug Design,College of Pharmacy,University of Minnesota,Minneapolis,MN 55455,USA [2]Translational Medicine R&D Center,Shenzhen Institutes of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第4期1671-1684,共14页药学学报（英文版）

基　　金：This research was supported by the National Institute of Allergy and Infectious Diseases,the National Institutes of Health,United States grant number R01AI136982(to Robert J.Geraghty and Zhengqiang Wang,USA).

摘　　要：Current drugs for treating human cytomegalovirus(HCMV)infections are limited by resistance and treatment-associated toxicities.In developing mechanistically novel HCMV antivirals,we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit(8a)inhibiting HCMV in submicromolar range.We describe herein the structure–activity relationship(SAR)for 8a,and the characterization of potent analogs for cytotoxicity/cytostatic property,the preliminary mechanism of action,and the absorption,distribution,metabolism and excretion(ADME)properties.The SAR revealed a few pharmacophore features conferring optimal antiviral profile,including the 5-OH,the N-1 benzyl,at least one–CH_(2)−in the linker,and a di-halogen substituted phenyl ring in the amide moiety.In the end,we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index.The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay,a virus entry assay,a time-of-addition assay,and a compound withdrawal assay.ADME profiling measuring aqueous solubility,plasma and liver microsomal stability,and parallel artificial membrane permeability assay(PAMPA)permeability demonstrated largely favorable drug-like properties.Together,these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.

关 键 词：Human cytomegalovirus N-Benzyl hydroxypyridone carboxamides Structureeactivity relationship Mechanism of action 

分 类 号：R914[医药卫生—药物化学]