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

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1671-1684页

作者： Sameera Senaweera Tiffany C.Edwards Jayakanth Kankanala Yan Wang rajkumar lalji sahani Jiashu Xie Robert J.Geraghty Zhengqiang Wang Center for Drug Design College of PharmacyUniversity of MinnesotaMinneapolisMN 55455USA Translational Medicine R&D Center Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

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

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Novel PF74-like small molecules targeting the HIV-1 capsid protein:Balance of potency and metabolic stability

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Acta Pharmaceutica Sinica B 2021年第3期11卷 810-822页

作者： Lei Wang Mary CCasey Sanjeev Kumar VVernekar rajkumar lalji sahani Karen AKirby Haijuan Du Huanchun Zhang Philip RTedbury Jiashu Xie Stefan GSarafianos Zhengqiang Wang Center for Drug Design College of PharmacyUniversity of MinnesotaMN 55455USA Department of Pharmaceutical Sciences School of Chemical EngineeringDalian University of TechnologyDalian 116024China Department of Molecular Microbiology and Immunology University of Missouri School of MedicineChristopher S.Bond Life Sciences CenterColumbiaMO 65211USA Laboratory of Biochemical Pharmacology Department of PediatricsEmory University School of MedicineAtlantaGA 30322USA

Of all known small molecules targeting human immunodeficiency virus(HIV)capsid protein(CA),PF74 represents by far the best characterized chemotype,due to its ability to confer antiviral phenotypes in both early and late phases of viral replication.However,the prohibitively low metabolic stability renders PF74 a poor antiviral lead.We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site.Specifically,we replaced the inter-domain-interacting,electron-rich indole ring of PF74 with less electron-rich isosteres,including imidazolidine-2,4-dione,pyrimidine-2,4-dione,and benzamide,and identified four potent antiviral compounds(10,19,20 and 26)with markedly improved metabolic stability.Compared to PF74,analog 20 exhibited similar submicromolar potency,and much longer(51-fold)half-life in human liver microsomes(HLMs).Molecular docking corroborated that 20 binds to the PF74 binding site,and revealed distinct binding interactions conferred by the benzamide moiety.Collectively,our data support compound 20 as a promising antiviral lead.

关键词： HIV-1 Capsid protein PF74 Microsomal stability

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