Lowden C T, Bastow K F
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, CB# 7630, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Antiviral Res. 2003 Aug;59(3):143-54. doi: 10.1016/s0166-3542(03)00106-2.
The synthetic acridone compound, 5-chloro-1,3-dihydroxyacridone inhibits herpes simplex virus (HSV) replication by inducing the formation of defective viral (B-type) capsids [Antiviral Res. 53 (2002) 113]. In this report, synthetic elaboration of the 1-hydroxyacridone scaffold coupled with antiviral testing led to the identification of 3,7-dimethoxy-1-hydroxy-acridone (2) as an inhibitor of low multiplicity human cytomegalovirus (HCMV) infection (ED(50) value of 1.4 microM (0.5 microg/ml); greater than 35-fold selectivity). Compound 2 was inactive against HSV replication and the efficacy as an anti-HCMV agent at higher viral loads was only apparent if host cells were replicated in the presence of the compound prior to infection. Interestingly, the 3,5-dimethoxy regioisomer inhibited cell replication (mean CC(50) 33 microM) and was inactive as a selective anti-herpes agent. A limited parallel synthesis and testing of ten 3,7-dialkoxylated compounds closely related to compound 2 led to the discovery of the 3-ethoxy-, 3-propoxy-, 3-isopropoxy- and 3-allyloxy-derivatives as dual inhibitors of both HSV and HCMV (selectivity of the 3-allyloxy analog was greater than 10- and 36-fold, respectively). The 3-benzyloxy-derivative was active (ED(50) value of 6.9 microM) against HCMV only. Moreover, the corresponding C-7 variable alkoxylated parallel series were either weakly active or inactive antiviral agents suggesting an apparent requirement for a C-7 methoxy substituent in the active structure. Exploratory mode of action studies showed that dual inhibitors were most active against a low multiplicity HSV infection and potent inhibition of viral release likely contributed to this. Furthermore, suppression of late viral protein synthesis by dual inhibitors did not correlate with anti-HSV activity. On the basis of the present findings, the 1-hydroxyacridone scaffold is further expanded as a useful template for the discovery of investigational anti-herpes agents. As a group, the active 3,7-dialkoxylated compounds likely have diverse mechanisms of action, consequently they are of potential medicinal interest.
合成吖啶酮化合物5-氯-1,3-二羟基吖啶酮通过诱导缺陷病毒（B型）衣壳的形成来抑制单纯疱疹病毒（HSV）复制[《抗病毒研究》53（2002）113]。在本报告中，对1-羟基吖啶酮骨架进行合成修饰并结合抗病毒测试，确定3,7-二甲氧基-1-羟基吖啶酮（2）为低 multiplicity 人巨细胞病毒（HCMV）感染的抑制剂（ED50值为1.4 microM（0.5 microg/ml）；选择性大于35倍）。化合物2对HSV复制无活性，并且只有在感染前宿主细胞在该化合物存在下进行复制时，其作为抗HCMV药物在更高病毒载量下的疗效才会显现。有趣的是，3,5-二甲氧基区域异构体抑制细胞复制（平均CC50为33 microM），并且作为选择性抗疱疹药物无活性。对与化合物2密切相关的十种3,7-二烷氧基化化合物进行有限的平行合成和测试，发现3-乙氧基、3-丙氧基、3-异丙氧基和3-烯丙氧基衍生物是HSV和HCMV的双重抑制剂（3-烯丙氧基类似物的选择性分别大于10倍和36倍）。3-苄氧基衍生物仅对HCMV有活性（ED50值为6.9 microM）。此外，相应的C-7可变烷氧基化平行系列要么是弱活性抗病毒剂，要么是无活性抗病毒剂，这表明活性结构中明显需要C-7甲氧基取代基。探索性作用方式研究表明，双重抑制剂对低 multiplicity HSV感染最具活性，对病毒释放的有效抑制可能对此有贡献。此外，双重抑制剂对晚期病毒蛋白合成的抑制与抗HSV活性无关。基于目前的研究结果，1-羟基吖啶酮骨架作为发现研究性抗疱疹药物的有用模板得到进一步扩展。作为一个整体，活性3,7-二烷氧基化化合物可能具有多种作用机制，因此它们具有潜在的药用价值。
