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Scaffold hopping and optimisation of 3’,4’-dihydroxyphenyl- containing thienopyrimidinones: synthesis of quinazolinone derivatives as novel allosteric inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2020-11-03 , DOI: 10.1080/14756366.2020.1835884
Graziella Tocco 1 , Francesca Esposito 1 , Pierluigi Caboni 1 , Antonio Laus 1 , John A. Beutler 2 , Jennifer A. Wilson 2 , Angela Corona 1 , Stuart F. J. Le Grice 3 , Enzo Tramontano 1
Affiliation  

Abstract

Bioisosteric replacement and scaffold hopping are powerful strategies in drug design useful for rationally modifying a hit compound towards novel lead therapeutic agents. Recently, we reported a series of thienopyrimidinones that compromise dynamics at the p66/p51 HIV-1 reverse transcriptase (RT)-associated Ribonuclease H (RNase H) dimer interface, thereby allosterically interrupting catalysis by altering the active site geometry. Although they exhibited good submicromolar activity, the isosteric replacement of the thiophene ring, a potential toxicophore, is warranted. Thus, in this article, the most active 2-(3,4-dihydroxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one 1 was selected as the hit scaffold and several isosteric substitutions of the thiophene ring were performed. A novel series of highly active RNase H allosteric quinazolinone inhibitors was thus obtained. To determine their target selectivity, they were tested against RT-associated RNA-dependent DNA polymerase (RDDP) and integrase (IN). Interestingly, none of the compounds were particularly active on (RDDP) but many displayed micromolar to submicromolar activity against IN.



中文翻译:

支架跳跃和优化3',4'-二羟基苯基的噻吩并嘧啶酮类化合物:喹唑啉酮衍生物的合成作为HIV-1逆转录酶相关核糖核酸酶H的新型变构抑制剂

摘要

生物甾体置换和支架跳跃是药物设计中的有效策略,可用于合理地将命中化合物修饰为新型先导治疗剂。最近,我们报道了一系列噻吩并嘧啶酮,它们破坏了与p66 / p51 HIV-1逆转录酶(RT)相关的核糖核酸酶H(RNase H)二聚体界面的动力学,从而通过改变活性位点的几何构型来中断催化作用。尽管它们表现出良好的亚微摩尔活性,但仍应等位取代噻吩环,这是一种潜在的毒性基团。因此,在本文中,活性最高的2-(3,4-二羟基苯基)-5,6-二甲基噻吩并[2,3-d]嘧啶-4(3 H-1选择被选为命中支架,并进行噻吩环的几个等位取代。因此获得了一系列新的高活性RNase H变构喹唑啉酮抑制剂。为了确定其靶标选择性,针对RT相关RNA依赖性DNA聚合酶(RDDP)和整合酶(IN)进行了测试。有趣的是,没有一种化合物对(RDDP)具有特别的活性,但是许多化合物对IN具有微摩尔至亚微摩尔的活性。

更新日期:2020-11-04
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