title: Mutagenicity of new lead compounds to treat sickle cell disease symptoms in a Salmonella/microsome assay.
abstract: A series of phthalimide derivatives planned as drugs candidates to treat the symptoms of sickle cell anemia were evaluated in a mutagenicity test using strains of Salmonella typhimurium TA100 and TA102, without and with addition of S9 mixture, with the aim to identify the best structural requirements for a drug candidate without genotoxic activity. The compounds (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (1); (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (2); 3-(1,3-dioxo-1,3-dihydro-2H-iso-indol-2-yl)benzyl nitrate (3); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (4); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (5) and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (6) presented mutagenic potency ranging between 0-4,803 revertants/micromol. These results allowed us to propose that a methyl spacer linked to a nitrate ester subunit associated to meta aromatic substitution decreases mutagenicity.
authors.affiliation: Departamento de Fármacos e Medicamentos, Univ Estadual Paulista-UNESP, Araraquara, SP, Brazil. santosjl@fcfar.unesp.br <santosjl@fcfar.unesp.br>
authors.forename: Jean Leandro
authors.initials: JL
authors.lastname: dos Santos
authors.forename: Eliana A
authors.initials: EA
authors.lastname: Varanda
authors.forename: Lídia Moreira
authors.initials: LM
authors.lastname: Lima
authors.forename: Chung Man
authors.initials: CM
authors.lastname: Chin
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy; D000818:Animals; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009152:Mutagenicity Tests; D010797:Phthalimides / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D010797:Phthalimides; C037431:phthalimide
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