Design and Synthesis of Novel Dihydroxyindole-2-Carboxylic Acids as HIV-1 Integrase Inhibitors

Sechi, Mario; Angotzi, Gianfranco; Dallocchio, Roberto; Dessì, Alessandro; Carta, Fabrizio; Sannia, Luciano; Mariani, A; Fiori, Stefano; Sanchez, Tino W.; Movsessian, Leah; Plasencia, Carmen; Neamati, Nouri

doi:10.1177/095632020401500203

Cited by 28 publications

(19 citation statements)

References 45 publications

(43 reference statements)

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“…[50,51] Figure 6. Amides derived from 2 and aliphatic/cycloaliphatic diamines for the production of hyperbranched architectures containing moieties based on 2.…”

Section: Synthesis and Functionalizationmentioning

confidence: 97%

5,6‐Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin

2011

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Keywords: Nitrogen heterocycles / Oxidation / Oligomers / Polymers / Melanin biopolymers / Bioinspired products / Nanostructures / Conducting materials 5,6-Dihydroxyindoles, the key building blocks of eumelanin biopolymers, hold promise as versatile molecular systems for the design and development of new functional aromatic scaffolds, biomimetic polymers, and nanomaterials with tailored optical and electronic properties. During the past decade, research into the photophysics, synthesis, π electron manipulation, and reaction behavior of 5,6-dihydroxyindoles has expanded beyond the traditional boundaries of biology and medicine to involve physicists, organic chemists, and materi-

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“…[50,51] Figure 6. Amides derived from 2 and aliphatic/cycloaliphatic diamines for the production of hyperbranched architectures containing moieties based on 2.…”

Section: Synthesis and Functionalizationmentioning

confidence: 97%

5,6‐Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin

2011

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“…Calculations were carried out with the method that we previously used and validated for the HIV-1 integrase protein (42)(43)(44)(45), with relevant modifications. Binding of the compound was analyzed using AutoDockTools 1.5.6 (46,47) and AutoDock 4.2 (47,48).…”

Section: Methodsmentioning

confidence: 99%

Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

Stevaert

Dallocchio

Dessì

et al. 2013

J Virol

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The influenza virus PA endonuclease, which cleaves capped host pre-mRNAs to initiate synthesis of viral mRNA, is a prime target for antiviral therapy. The diketo acid compound L-742,001 was previously identified as a potent inhibitor of the influenza virus endonuclease reaction, but information on its precise binding mode to PA or potential resistance profile is limited. Computer-assisted docking of L-742,001 into the crystal structure of inhibitor-free N-terminal PA (PA-Nter) indicated a binding orientation distinct from that seen in a recent crystallographic study with L-742,001-bound PA-Nter (R. M. DuBois et al., PLoS Pathog. 8:e1002830, 2012). A comprehensive mutational analysis was performed to determine which amino acid changes within the catalytic center of PA or its surrounding hydrophobic pockets alter the antiviral sensitivity to L-742,001 in cell culture. Marked (up to 20-fold) resistance to L-742,001 was observed for the H41A, I120T, and G81F/V/T mutant forms of PA. Two-to 3-fold resistance was seen for the T20A, L42T, and V122T mutants, and the R124Q and Y130A mutants were 3-fold more sensitive to L-742,001. Several mutations situated at noncatalytic sites in PA had no or only marginal impact on the enzymatic functionality of viral ribonucleoprotein complexes reconstituted in cell culture, consistent with the less conserved nature of these PA residues. Our data provide relevant insights into the binding mode of L-742,001 in the PA endonuclease active site. In addition, we predict some potential resistance sites that should be taken into account during optimization of PA endonuclease inhibitors toward tight binding in any of the hydrophobic pockets surrounding the catalytic center of the enzyme.

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“…60 These compounds were designed as conformationally constrained analogs of the acrylate moiety of caffeic acid phenethyl ester (CAPE) (Fig. 17).…”

Section: Miscellaneous Compoundsmentioning

confidence: 99%

HIV‐1 integrase inhibitors: 2003–2004 update

Dayam

Deng

Neamati

2006

Medicinal Research Reviews

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The integration of viral cDNA into the host genome is an essential step in the HIV-1-life cycle and is mediated by the virally encoded enzyme, integrase (IN). Inhibition of this process provides an attractive strategy for antiviral drug design. The discovery of beta-diketo acid inhibitors played a major role in validating IN as a legitimate antiretroviral drug target. Over a decade of research, a plethora of IN inhibitors have been discovered and some showed antiviral activity consistent with their effect on IN. To date, at least two compounds have been tested in human but none are close to the FDA approval. In this review, we provide a comprehensive report of all small-molecule IN inhibitors discovered during the years 2003 and 2004. Compilation of such data will prove beneficial in developing QSAR, virtual screening, pharmacophore hypothesis generation, and validation.

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Design and Synthesis of Novel Dihydroxyindole-2-Carboxylic Acids as HIV-1 Integrase Inhibitors

Cited by 28 publications

References 45 publications

5,6‐Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin

5,6‐Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin

Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

HIV‐1 integrase inhibitors: 2003–2004 update

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