Boiani Mariana, Boiani Lucía, Denicola Ana, Torres de Ortiz Susana, Serna Elva, Vera de Bilbao Ninfa, Sanabria Luis, Yaluff Gloria, Nakayama Héctor, Rojas de Arias Antonieta, Vega Celeste, Rolan Miriam, Gómez-Barrio Alicia, Cerecetto Hugo, Gonzalez Mercedes
Departamento de Química Organica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Uruguay.
J Med Chem. 2006 Jun 1;49(11):3215-24. doi: 10.1021/jm0600343.
Three series of benzimidazole N-oxide derivatives were developed and were examined for their activity against trypanosomatid parasites (Trypanosoma cruzi and Leishmania spp.). 2H-benzimidazole 1,3-dioxides displayed remarkable in vitro activities against both parasites, with derivatives 28, 29, and 32 being the most potent (IC50 < 5 microM) against the epimastigote form of T. cruzi and 28, 33, and 35 the most potent against the promastigote form of Leishmania spp. Unspecific cytotoxicity was evaluated using murine macrophages, and derivative 33 was not toxic at a concentration 30 times that of its IC50 against T. cruzi that was completely toxic for Leishmania spp., implying that the series of 2H-benzimidazole 1,3-dioxides is selective toward both trypanosomatid parasites. Derivatives 33 and 35 were submitted to an in vivo assay using an acute model of Chagas' disease and a short-term treatment (30 mg/kg/day orally administrated as aqueous solution, during 10 days). While in the control (untreated) and Benznidazole (50 mg/kg/day) groups survival fraction was 60.0% and 87.5%, respectively, none of the animals treated with derivatives 33 and 35 died. From the preliminary structure-activity relationship studies reduction potential and electrophilicity were found relevant to anti-T. cruzi activity. Active compounds are better electrophiles and more easily reduced than inactive ones.
开发了三类苯并咪唑N-氧化物衍生物，并检测了它们对锥虫寄生虫（克氏锥虫和利什曼原虫属）的活性。2H-苯并咪唑1,3-二氧化物对这两种寄生虫均表现出显著的体外活性，其中衍生物28、29和32对克氏锥虫的无鞭毛体形式活性最强（IC50 < 5 microM），而28、33和35对利什曼原虫属的前鞭毛体形式活性最强。使用小鼠巨噬细胞评估了非特异性细胞毒性，衍生物33在浓度为其对克氏锥虫IC50的30倍时无毒，而该浓度对利什曼原虫属具有完全毒性，这意味着2H-苯并咪唑1,3-二氧化物系列对这两种锥虫寄生虫具有选择性。衍生物33和35使用恰加斯病急性模型进行了体内试验，并进行了短期治疗（以水溶液形式口服给药，30 mg/kg/天，持续10天）。在对照组（未治疗）和苯硝唑（50 mg/kg/天）组中，存活分数分别为60.0%和87.5%，而用衍生物33和35治疗的动物均未死亡。从初步的构效关系研究中发现，还原电位和亲电性与抗克氏锥虫活性相关。活性化合物比非活性化合物是更好的亲电试剂，且更容易被还原。
