Institute of Organic and Analytical Chemistry (ICOA UMR 7311), University of Orleans, CNRS, F-45067 Orléans, France.
Institute of Organic and Analytical Chemistry (ICOA UMR 7311), University of Orleans, CNRS, F-45067 Orléans, France.
Eur J Med Chem. 2024 May 5;271:116412. doi: 10.1016/j.ejmech.2024.116412. Epub 2024 Apr 15.
New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC 0.0035 μM, SI 740) and for thymidine kinase VZV deficient strains (EC 0.018 μM, SI 145), with a low morphological toxicity in cell culture at 100 μM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited antiviral activity against HCMV (EC 0.021 μM) and VV (EC 0.050 μM), as well as against HSV-1 (TK-) (EC 0.0085 μM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug.
新的无环嘧啶核苷膦酸前药具有 4-(2,4-二氨基嘧啶-6-基)氧基-丁-2-烯基]膦酸骨架（O-DAPy 碱基），通过关键步骤的烯烃交叉复分解反应通过收敛合成制备。几种无环核苷 4-(2,4-二氨基嘧啶-6-基)氧基-丁-2-烯基]膦酸前药在亚微摩尔或纳摩尔范围内对水痘带状疱疹病毒（VZV）、人巨细胞病毒（HCMV）、单纯疱疹病毒 1 型（HSV-1）和 2 型（HSV-2）和牛痘病毒（VV）表现出体外抗病毒活性，具有良好的选择性指数（SI）。其中，类似物 9c（LAVR-289）对 VZV 野生型（TK+）（EC 0.0035 μM，SI 740）和胸苷激酶 VZV 缺乏株（EC 0.018 μM，SI 145）具有明显的抑制作用，在 100 μM 时在细胞培养物中具有低形态毒性和可接受的细胞抑制活性，从而具有优异的选择性。化合物 9c 对 HCMV（EC 0.021 μM）和 VV（EC 0.050 μM）以及 HSV-1（TK-）（EC 0.0085 μM）具有抗病毒活性。最后，LAVR-289（9c）作为一种有效的广谱抗疱疹病毒候选药物，值得进一步（临床前）研究。
