Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions

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• 作者：Paulo Renato Yamasaki^a ; Dejair Caetano do Nascimento^b ; Rafael Consolin Chelucci^a ; André ; a de Faria Fernandes Belone^b ; Patrí ; cia Sammarco Rosa^b ; Suzana Madeira Dió ; rio^b ; Thais Regina Ferreira de Melo^a ; Karina Pereira Barbieri^a ; Marisa Campos Polé ; si Placeres^a ; Iracilda Zepone Carlos^a ; Man Chin Chung^a ; Jean Leandro dos Santos^a ; ^{santosjl@fcfar.unesp.br" class="auth_mail}
• 关键词：Leprosy ; M. leprae ; Anti-inflammatory ; Analgesic ; TNF伪 ; Dapsone ; Thalidomide ; Molecular hybridization ; Erythema nodosum leprosum
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 July 2014
• 年：2014
• 卷：24
• 期：14
• 页码：3084-3087
• 全文大小：573 K

文摘

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-伪 levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 渭M, compound 3i decreased tumor necrosis factor-伪 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.