Guedes-da-Silva F H, Batista D G J, Meuser M B, Demarque K C, Fulco T O, Araújo J S, Da Silva P B, Da Silva C F, Patrick D A, Bakunova S M, Bakunov S A, Tidwell R R, Oliveira G M, Britto C, Moreira O C, Soeiro M N C
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
University of North Carolina, Chapel Hill, North Carolina, USA.
Antimicrob Agents Chemother. 2016 Mar 25;60(4):2425-34. doi: 10.1128/AAC.01667-15. Print 2016 Apr.
Arylimidamides (AIAs) have been shown to have considerable biological activity against intracellular pathogens, includingTrypanosoma cruzi, which causes Chagas disease. In the present study, the activities of 12 novel bis-AIAs and 2 mono-AIAs against different strains ofT. cruziin vitroandin vivowere analyzed. The most active wasm-terphenyl bis-AIA (35DAP073), which had a 50% effective concentration (EC50) of 0.5 μM for trypomastigotes (Y strain), which made it 26-fold more effective than benznidazole (Bz; 13 μM). It was also active against the Colombiana strain (EC50= 3.8 μM). Analysis of the activity against intracellular forms of the Tulahuen strain showed that this bis-AIA (EC50= 0.04 μM) was about 100-fold more active than Bz (2 μM). The trypanocidal effect was dissociated from the ability to trigger intracellular lipid bodies within host cells, detected by oil red labeling. Both an active compound (35DAP073) and an inactive compound (26SMB060) displayed similar activation profiles. Due to their high selectivity indexes, two AIAs (35DAP073 and 35DAP081) were moved toin vivostudies, but because of the results of acute toxicity assays, 35DAP081 was excluded from the subsequent tests. The findings obtained with 35DAP073 treatment of infections caused by the Y strain revealed that 2 days of therapy induced a dose-dependent action, leading to 96 to 46% reductions in the level of parasitemia. However, the administration of 10 daily doses in animals infected with the Colombiana strain resulted in toxicity, preventing longer periods of treatment. The activity of the combination of 0.5 mg/kg of body weight/day 35DAP073 with 100 mg/kg/day Bz for 10 consecutive days was then assayed. Treatment with the combination resulted in the suppression of parasitemia, the elimination of neurological toxic effects, and survival of 100% of the animals. Quantitative PCR showed a considerable reduction in the parasite load (60%) compared to that achieved with Bz or the amidine alone. Our results support further investigations of this class with the aim of developing novel alternatives for the treatment of Chagas disease.
芳基咪唑酰胺（AIA）已被证明对包括导致恰加斯病的克氏锥虫在内的细胞内病原体具有显著的生物活性。在本研究中，分析了12种新型双AIA和2种单AIA对不同克氏锥虫菌株的体外和体内活性。活性最强的是间三联苯双AIA（35DAP073），其对锥鞭毛体（Y株）的50%有效浓度（EC50）为0.5μM，比苯并硝唑（Bz；13μM）有效26倍。它对哥伦比亚株也有活性（EC50 = 3.8μM）。对图拉亨株细胞内形式的活性分析表明，这种双AIA（EC50 = 0.04μM）的活性比Bz（2μM）高约100倍。通过油红染色检测，杀锥虫作用与触发宿主细胞内脂质体的能力无关。活性化合物（35DAP073）和非活性化合物（26SMB060）均表现出相似的激活特征。由于其高选择性指数，两种AIA（35DAP073和35DAP081）进入体内研究，但由于急性毒性试验结果，35DAP081被排除在后续试验之外。用35DAP073治疗Y株引起的感染的结果显示，2天的治疗诱导了剂量依赖性作用，导致寄生虫血症水平降低96%至46%。然而，对感染哥伦比亚株的动物每日给药10次会导致毒性，无法进行更长时间的治疗。然后测定了连续10天每天0.5mg/kg体重的35DAP073与每天100mg/kg的Bz联合用药的活性。联合治疗导致寄生虫血症得到抑制，神经毒性作用消除，100%的动物存活。定量PCR显示，与单独使用Bz或脒相比，寄生虫负荷显著降低（60%）。我们的结果支持对这一类药物进行进一步研究，以开发治疗恰加斯病的新替代药物。
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