Chemical Modification of Coumarin Dimer and HIV-1 Integrase Inhibitory Activity.

Mao, Pili Chih-Min; Mouscadet, Jean‐François; Leh, Hervé; Auclair, Christian; Hsu, Ling-Yih

doi:10.1248/cpb.50.1634

Cited by 64 publications

(40 citation statements)

References 20 publications

(15 reference statements)

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“…In addition, several benzoic acids were Several coumarin dimers, one of the most extensively described classes of IN inhibitors, were also identified in this screen. The IC 50 values we report are, in fact, surprisingly close to those previously reported for similar coumarin derivatives (29,43). Our results provide the first evidence that coumarins inhibit Tn5 Tnp, indicating that coumarins are interacting with a conserved region of these proteins.…”

Section: Discussionsupporting

confidence: 89%

Targeting Tn 5 Transposase Identifies Human Immunodeficiency Virus Type 1 Inhibitors

Ason

Knauss

Balke

et al. 2005

Antimicrob Agents Chemother

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Human immunodeficiency virus (HIV) type 1 (HIV-1) integrase is an underutilized drug target for the treatment of HIV infection. One limiting factor is the lack of costructural data for use in the rational design or modification of integrase inhibitors. Tn5 transposase is a structurally well characterized, related protein that may serve as a useful surrogate. However, little data exist on inhibitor cross-reactivity. Here we screened 16,000 compounds using Tn5 transposase as the target and identified 20 compounds that appear to specifically inhibit complex assembly. Six were found to also inhibit HIV-1 integrase. These compounds likely interact with a highly conserved region presumably within the catalytic core. Most promising, several cinnamoyl derivatives were found to inhibit HIV transduction in cells. The identification of integrase inhibitors from a screen using Tn5 transposase as the target illustrates the utility of Tn5 as a surrogate for HIV-1 integration even though the relationship between the two systems is limited to the active site architecture and catalytic mechanism.Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is a high-valued candidate in the search for new targets to treat human immunodeficiency virus (HIV) infection. IN is responsible for integrating the viral genome into the host, a required step in the viral life cycle (reviewed in references 2, 10, 11, and 19). IN, however, is underutilized for treatment, as only one drug targeting this protein, S-1360, is currently under clinical trials (5), while a second has recently been shown to be effective for rhesus macaques (25). Such candidates would be invaluable to complement existing reverse transcriptase and protease inhibitors used in highly active antiretroviral therapy, the multidrug regime that attenuates HIV.Many compounds have been identified that inhibit IN in vitro. However, few have been identified that are both specific for IN and effective in cell culture (34). The lack of cocrystal structural information currently available to map critical INinhibitor contacts is one limiting factor in the identification of good drug candidates. This information would aid in the rational design or modification of known IN inhibitors to develop more effective therapeutic agents. To date, only partial IN structures have been solved (6,7,9,18,21,22,27,28,40,42) and only two inhibitor classes, diketo and naphthalene derivatives, have been cocrystallized with members of the IN family (21, 27).Due to these constraints, the Tn5 transposase (Tnp) may serve as an excellent surrogate model for IN. Tn5 Tnp is the most extensively structurally characterized member of the Tnp/IN superfamily of proteins (reviewed in references 4 and 13), and although these proteins have low amino acid sequence identity, they share a high degree of structural similarity (4,7,15,18,36,40). The catalytic core of this superfamily exhibits an alpha-beta-alpha fold, where two sets of two alpha-helices flank a region of antiparallel beta sheet. Located within this region are...

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Section: Discussionsupporting

confidence: 89%

Targeting Tn 5 Transposase Identifies Human Immunodeficiency Virus Type 1 Inhibitors

Ason

Knauss

Balke

et al. 2005

Antimicrob Agents Chemother

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“…Some coumarin derivatives were proven to be a superior antioxidant agent [15]. Structure modification of coumarin moiety exhibit inhibition of unit enzyme both in vitro and in vivo [16][17][18][19][20]. Corrosion inhibitors increase the impedance of mild steel toward corrosive solutions and inhibit or retard the corrosion through adsorbing the molecules of inhibitor on the surface of mild steel [21][22][23][24][25][26][27] in order to generate a barrier on the surface that block dynamic sites for mild steel [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

New Corrosion Inhibitor Derived from Coumarin

Al-Amiery¹

2017

Preprint

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New corrosion inhibitor derived from coumarin-3-amine namely 3-((2-chlorobenzylidene)amino)coumarin was synthesized and characterized by CHN elemental analysis in addition to Fourier transform infrared and nuclear magnetic resonance techniques. The anticorrosion ability of 3-((2-chlorobenzylidene)amino)coumarin to inhibit the impacts of corrosion has been demonstrated and damage reduction of the mild steel also. 3-((2-chlorobenzylidene)amino)coumarin, has been employed as a good corrosion inhibitor for mild steel in HCL solution. The efficiency of the inhibition was figured according to weight loss method and it was 74.6%.

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“…However, these compounds did not markedly increase the inhibitory activity and seemed to fail forming covalent binding at coumarin-IN complex binding site. We also reported biscoumarins with a diversified modification on the linker 18) and enabled us to know that the benzoyloxyphenyl linker (III) seemed important for the inhibitory activity. These encouraging results prompted us to modify these lead compounds.…”

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confidence: 91%

Synthesis and HIV-1 Integrase Inhibition of Novel Bis- or Tetra-Coumarin Analogues

Chiang¹,

Mouscadet

Tsai³

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Chemical Modification of Coumarin Dimer and HIV-1 Integrase Inhibitory Activity.

Abstract: A systematic series of chemically modified coumarin dimmers has been synthesized and tested for their inhibitory activity against HIV-1 integrase. We observed that modified coumarin dimmers containing hydrophobic moiety on the linker display potent inhibitory activities.

Cited by 64 publications

References 20 publications

Targeting Tn 5 Transposase Identifies Human Immunodeficiency Virus Type 1 Inhibitors

Targeting Tn 5 Transposase Identifies Human Immunodeficiency Virus Type 1 Inhibitors

New Corrosion Inhibitor Derived from Coumarin

Synthesis and HIV-1 Integrase Inhibition of Novel Bis- or Tetra-Coumarin Analogues

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