Bisnaphthalimidopropyl derivatives as inhibitors of Leishmania SIR2 related protein 1

ChemMedChem
J TavaresA Cordeiro-da-Silva

Abstract

The NAD(+)-dependent deacetylases, namely sirtuins, are involved in the regulation of a variety of biological processes such as gene silencing, DNA repair, longevity, metabolism, apoptosis, and development. An enzyme from the parasite Leishmania infantum that belongs to this family, LiSIR2RP1, is a NAD(+)-dependent tubulin deacetylase and an ADP-ribosyltransferase. This enzyme's involvement in L. infantum virulence and survival underscores its potential as a drug target. Our search for selective inhibitors of LiSIR2RP1 has led, for the first time, to the identification of the antiparasitic and anticancer bisnaphthalimidopropyl (BNIP) alkyl di- and triamines (IC(50) values in the single-digit micromolar range for the most potent compounds). Structure-activity studies were conducted with 12 BNIP derivatives that differ in the length of the central alkyl chain, which links the two naphthalimidopropyl moieties. The most active and selective compound is the BNIP diaminononane (BNIPDanon), with IC(50) values of 5.7 and 97.4 microM against the parasite and human forms (SIRT1) of the enzyme, respectively. Furthermore, this compound is an NAD(+)-competitive inhibitor that interacts differently with the parasite and human enzymes, as det...Continue Reading

References

Jul 29, 2000·Bioorganic & Medicinal Chemistry Letters·P K Lin, V A Pavlov
Mar 21, 2001·Antimicrobial Agents and Chemotherapy·D SerenoM Ouellette
Jun 28, 2001·Nature Structural Biology·M S FinninN P Pavletich
Oct 24, 2001·Cell·H VaziriR A Weinberg
Dec 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·A BedalovJ A Simon
Oct 29, 2002·Nature Genetics·Oksana R BereshchenkoRiccardo Dalla-Favera
Mar 7, 2003·Molecular Cell·Brian J NorthEric Verdin
Aug 27, 2003·Nature·Konrad T HowitzDavid A Sinclair
Oct 3, 2003·The Journal of Biological Chemistry·Michael D JacksonJohn M Denu
Apr 14, 2004·Current Medicinal Chemistry·Anthony A Sauve, Vern L Schramm
Jul 30, 2004·Molecular and Cellular Biology·Jason C TannyDanesh Moazed
Feb 19, 2005·PLoS Biology·Sara PagansMelanie Ott
Mar 30, 2005·The Journal of Biological Chemistry·Gregory LisztLeonard Guarente
May 3, 2005·International Journal for Parasitology·J TavaresA Cordeiro-da-Silva
Dec 13, 2005·Journal of Medicinal Chemistry·Andrew D NapperRory Curtis
Sep 20, 2006·Bioorganic & Medicinal Chemistry Letters·Rameshwar U KadamNilanjan Roy
Dec 8, 2006·Journal of Medicinal Chemistry·Johannes TrappManfred Jung
Mar 16, 2007·Structure·Anja SchuetzAlexander N Plotnikov
Jun 26, 2007·Science·Tiago Fleming OuteiroAleksey G Kazantsev

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Citations

Nov 30, 2011·Immunology and Cell Biology·Katherine T AndrewsMalcolm K Jones
Sep 29, 2012·Current Pharmaceutical Design·Santina BruzzoneAlessio Nencioni
Oct 24, 2013·Expert Opinion on Drug Delivery·Shalini AsthanaManish K Chourasia
Dec 12, 2012·European Journal of Medicinal Chemistry·Weiping Zheng
Mar 9, 2012·International Journal of Antimicrobial Agents·Sofia Costa LimaAnabela Cordeiro da Silva
Jul 6, 2010·Biochimica Et Biophysica Acta·Michael LawsonWolfgang Sippl
Dec 14, 2011·Parasitology International·Joana TavaresAnabela Cordeiro-da-Silva
May 23, 2015·Future Medicinal Chemistry·Julien LancelotRaymond J Pierce
Aug 22, 2012·Molecular and Biochemical Parasitology·Agnieszka A Religa, Andrew P Waters
Feb 28, 2017·Journal of Medicinal Chemistry·Gebremedhin S HailuAntonello Mai
Nov 30, 2011·Memórias do Instituto Oswaldo Cruz·Raymond John PierceEmmanuel Roger
Jan 21, 2016·Antimicrobial Agents and Chemotherapy·Nuno A G GraçaAnabela Cordeiro-da-Silva
Apr 14, 2016·Antimicrobial Agents and Chemotherapy·Ylenia BaquedanoCarmen Sanmartín
Mar 13, 2014·Expert Review of Vaccines·Shyam Sundar, Bhawana Singh
Jan 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Elif KeskinMustafa Guzel
Dec 28, 2016·Archiv der Pharmazie·Ashwani Kumar, Shilpi Chauhan
Aug 16, 2018·MedChemComm·Michael BerningerUlrike Holzgrabe
Jan 23, 2018·PLoS Neglected Tropical Diseases·Luís GasparAnabela Cordeiro-da-Silva
Nov 18, 2010·Journal of Medicinal Chemistry·Charles A BlumRoss L Stein
May 12, 2020·Journal of Medicinal Chemistry·Victoriano Corpas-LópezJosé A Gómez-Vidal

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