title: Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions.
abstract: We synthesized a series of novel dapsone-thalidomide hybrids (3a-i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil.
authors.forename: Paulo Renato
authors.initials: PR
authors.lastname: Yamasaki
authors.affiliation: Instituto Lauro de Souza Lima, Rodovia Comandante João Ribeiro de Barros, Km 225/226, 17034-971 Bauru, SP, Brazil.
authors.forename: Dejair Caetano
authors.initials: DC
authors.lastname: do Nascimento
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil.
authors.forename: Rafael Consolin
authors.initials: RC
authors.lastname: Chelucci
authors.affiliation: Instituto Lauro de Souza Lima, Rodovia Comandante João Ribeiro de Barros, Km 225/226, 17034-971 Bauru, SP, Brazil.
authors.forename: Andréa
authors.initials: A
authors.lastname: de Faria Fernandes Belone
authors.affiliation: Instituto Lauro de Souza Lima, Rodovia Comandante João Ribeiro de Barros, Km 225/226, 17034-971 Bauru, SP, Brazil.
authors.forename: Patrícia Sammarco
authors.initials: PS
authors.lastname: Rosa
authors.affiliation: Instituto Lauro de Souza Lima, Rodovia Comandante João Ribeiro de Barros, Km 225/226, 17034-971 Bauru, SP, Brazil.
authors.forename: Suzana Madeira
authors.initials: SM
authors.lastname: Diório
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil.
authors.forename: Thais Regina Ferreira
authors.initials: TR
authors.lastname: de Melo
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil.
authors.forename: Karina Pereira
authors.initials: KP
authors.lastname: Barbieri
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil.
authors.forename: Marisa Campos Polési
authors.initials: MC
authors.lastname: Placeres
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil.
authors.forename: Iracilda Zepone
authors.initials: IZ
authors.lastname: Carlos
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil.
authors.forename: Man Chin
authors.initials: MC
authors.lastname: Chung
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, SP, Brazil. Electronic address: santosjl@fcfar.unesp.br.
authors.forename: Jean Leandro
authors.initials: JL
authors.lastname: dos Santos
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003622:Dapsone / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007918:Leprosy / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009166:Mycobacterium leprae / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013792:Thalidomide; D003622:Dapsone
keywords: Analgesic; Anti-inflammatory; Dapsone; Erythema nodosum leprosum; Leprosy; M. leprae; Molecular hybridization; TNFα; Thalidomide