Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120,ChemMedChem

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Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120
ChemMedChem ( IF 3.6 ) Pub Date : 2018-10-19 , DOI: 10.1002/cmdc.201800534
Francesca Curreli ₁ , Dmitry S. Belov ₂ , Shahad Ahmed ₁ , Ranjith R. Ramesh ₁ , Alexander V. Kurkin ₂ , Andrea Altieri ₂ , Asim K. Debnath ₁

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The pathway by which HIV‐1 enters host cells is a prime target for novel drug discovery because of its critical role in the life cycle of HIV‐1. The HIV‐1 envelope glycoprotein gp120 plays an important role in initiating virus entry by targeting the primary cell receptor CD4. We explored the substitution of bulky molecular groups in region I in the NBD class of entry inhibitors. Previous attempts at bulky substituents in that region abolished antiviral activity, even though the binding site is hydrophobic. We synthesized a series of entry inhibitors containing the 1,3‐benzodioxolyl moiety or its bioisostere, 2,1,3‐benzothiadiazole. The introduction of the bulkier groups was well tolerated, and despite only minor improvements in antiviral activity, the selectivity index of these compounds improved significantly.

中文翻译：

基于HIV-1 gp120中Phe43腔的1,3-苯并二氧戊基吡咯基的进入抑制剂的合成，抗病毒活性和构效关系。

HIV-1进入宿主细胞的途径是发现新药的主要目标，因为它在HIV-1的生命周期中起着至关重要的作用。HIV-1包膜糖蛋白gp120通过靶向原代细胞受体CD4在启动病毒进入中起重要作用。我们探索了NBD类进入抑制剂中I区中大分子基团的取代。即使该结合位点是疏水的，先前在该区域中的庞大取代基的尝试也消除了抗病毒活性。我们合成了一系列包含1,3-苯并二恶唑基部分或其生物等排体2,1,3-苯并噻二唑的进入抑制剂。引入大体积基团的耐受性良好，尽管抗病毒活性仅有微小改善，但这些化合物的选择性指数却显着提高。

更新日期：2018-10-19

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