title: Bisnaphthalimidopropyl derivatives as inhibitors of Leishmania SIR2 related protein 1.
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 determined by docking analysis, which might explain its selectivity toward the parasitic enzyme.
authors: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors: Joana
authors: J
authors: Tavares
authors: Ali
authors: A
authors: Ouaissi
authors: Paul
authors: P
authors: Kong Thoo Lin
authors: Inês
authors: I
authors: Loureiro
authors: Simranjeet
authors: S
authors: Kaur
authors: Nilanjan
authors: N
authors: Roy
authors: Anabela
authors: A
authors: Cordeiro-da-Silva
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D018314:Leishmania infantum / Q000201:enzymology*; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D053644:Naphthalimides; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins