106367-87-7Relevant academic research and scientific papers
Exploration of the 2,3-dihydroisoindole pharmacophore for inhibition of the influenza virus PA endonuclease
Rogolino, Dominga,Naesens, Lieve,Bartoli, Jennifer,Carcelli, Mauro,De Luca, Laura,Pelosi, Giorgio,Stokes, Ryjul W.,Van Berwaer, Ria,Vittorio, Serena,Stevaert, Annelies,Cohen, Seth M.
, (2021/10/14)
Seasonal influenza A and B viruses represent a global concern. Antiviral drugs are crucial to treat severe influenza in high-risk patients and prevent virus spread in case of a pandemic. The emergence of viruses showing drug resistance, in particular for the recently licensed polymerase inhibitor baloxavir marboxil, drives the need for developing alternative antivirals. The endonuclease activity residing in the N-terminal domain of the polymerase acidic protein (PAN) is crucial for viral RNA synthesis and a validated target for drug design. Its function can be impaired by molecules bearing a metal-binding pharmacophore (MBP) able to coordinate the two divalent metal ions in the active site. In the present work, the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold is explored for the inhibition of influenza virus PA endonuclease. The structure-activity relationship was analysed by modifying the substituents on the lipophilic moiety linked to the MBP. The new compounds exhibited nanomolar inhibitory activity in a FRET-based enzymatic assay, and a few compounds (15–17, 21) offered inhibition in the micromolar range, in a cell-based influenza virus polymerase assay. When investigated against a panel of PA-mutant forms, compound 17 was shown to retain full activity against the baloxavir-resistant I38T mutant. This was corroborated by docking studies providing insight into the binding mode of this novel class of PA inhibitors.
6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors
Zhao, Xue Zhi,Maddali, Kasthuraiah,Smith, Steven J.,Métifiot, Mathieu,Johnson, Barry C.,Marchand, Christophe,Hughes, Stephen H.,Pommier, Yves,Burke Jr., Terrence R.
supporting information, p. 7309 - 7313 (2013/02/21)
Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck's raltegravir and Gilead's elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The em
HYDRAZIDE, AMIDE, PHTHALIMIDE AND PHTHALHYDRAZIDE ANALOGS AS INHIBITORS OF RETROVIRAL INTEGRASE
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Page/Page column 34, (2009/04/25)
The present invention provides catechol-containing hydrazides, amides, phthalimide and phthalhydrazide analogs. These compounds are inhibitors of retroviral integrase, an essential enzyme for the proliferation of retroviruses such as HIV-1. Also provided are pharmaceutical compositions comprising at least one of the catechol-containing hydrazides, amides, phthalimide or phthalhydrazide analogs and a method of using the hydrazide, amide, phthalimide and phthalhydrazide analogs to inhibit retroviral proliferation and as therapeutics for the treatment of AIDS.
2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-based HIV-1 integrase inhibitors
Xue, Zhi Zhao,Semenova, Elena A.,Vu, B. Christie,Maddali, Kasthuraiah,Marchand, Christophe,Hughes, Stephen H.,Pommier, Yves,Burke Jr., Terrence R.
, p. 251 - 259 (2008/09/19)
The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1H- isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3′-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.
