Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV).
Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV).
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DOI：
10.1016/j.apsb.2021.08.019
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发表时间：
2022-04
影响因子：
14.5
通讯作者：
Wang, Zhengqiang
中科院分区：
文献类型：
--
作者：
Senaweera, Sameera;Edwards, Tiffany C.;Kankanala, Jayakanth;Wang, Yan;Sahani, Rajkumar Lalji;Xie, Jiashu;Geraghty, Robert J.;Wang, Zhengqiang
关键词：
目前用于治疗人巨细胞病毒（HCMV）感染的药物受到耐药性和治疗相关毒性的限制。在开发机理上新颖的HCMV抗病毒药物中，我们发现了N-苄基羟基吡啶酮甲酰胺抗病毒剂hit（8a）在亚微摩尔范围内抑制HCMV。我们在本文中描述了8a的结构-活性关系（SAR），以及有效类似物的细胞毒性/细胞抑制性质的表征，初步作用机制，以及吸收、分布、代谢和排泄（ADME）性质。SAR揭示了一些药效团特征，赋予了最佳的抗病毒特征，包括5-OH、N-1苄基、接头中的至少一个-CH 2 −和酰胺部分中的二卤素取代的苯环。最后，我们鉴定了许多具有亚微摩尔抗病毒效力和良好选择性指数的类似物。初步作用机制表征使用pUL 89-C生化内切核酸酶测定、病毒进入测定、添加时间测定和化合物撤回测定。测量水溶性、血浆和肝微粒体稳定性以及平行人工膜渗透性试验（PAMPA）渗透性的ADME分析显示了很大程度上有利的药物样性质。总之，这些研究验证了N-苄基羟基吡啶酮甲酰胺作为针对HCMV的有效和机制上不同的抗病毒药物的可行化学型。先前的HCMV pUL 89-C抑制剂的酰胺化（5）产生了机械上不同的新先导化合物（8a）。报道了8a的全面SAR和改进的类似物（12）的表征。
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 –CH2− 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. Amidation of a previous HCMV pUL89-C inhibitor (5) produced a mechanistically distinct new lead (8a). Comprehensive SAR of 8a, and the characterization of an improved analog (12) are reported.
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影响因子：
168.9
作者：
Gane, E;Saliba, F;Robinson, CA
通讯作者：
Robinson, CA
影响因子：
64.8
作者：
PAUWELS, R;ANDRIES, K;JANSSEN, PAJ
通讯作者：
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影响因子：
14.8
作者：
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通讯作者：
Pannecouque C
DOI：
10.4084/mjhid.2019.001
发表时间：
2019-01-01
影响因子：
3.2
作者：
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通讯作者：
Hilgendorf, Inken
影响因子：
4.9
作者：
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通讯作者：
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