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Bisnaphthalimidopropyl Derivatives as Inhibitors of Leishmania SIR2 Related Protein 1
Author(s) -
Tavares Joana,
Ouaissi Ali,
Kong Thoo Lin Paul,
Loureiro Inês,
Kaur Simranjeet,
Roy Nilanjan,
CordeirodaSilva Anabela
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900367
Subject(s) - nad+ kinase , enzyme , leishmania infantum , antiparasitic agent , biochemistry , biology , leishmania , docking (animal) , antiparasitic , chemistry , stereochemistry , parasite hosting , leishmaniasis , genetics , pharmacology , medicine , nursing , pathology , visceral leishmaniasis , world wide web , computer science
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 μ M 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 determined by docking analysis, which might explain its selectivity toward the parasitic enzyme.