Background: Although several research efforts have been made worldwide to discover novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol remains the only therapeutic alternative in the control of this disease. However, this drug presents reduced efficacy in the chronic form of the disease and limited safety after long periods of administration, making it necessary to search for new, more potent and safe prototypes.

Objective: We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi.

Methods: These compounds were designed through the application of molecular hybridization concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent in vitro as benznidazole.

Results: The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5- nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 μM) and the (Z)-N'-((E)-3-(4- hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85 μM), which were almost equipotent to benznidazole (IC50=10.26 μM) used as standard drug. The removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative (8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells from Swiss mice.

Conclusion: The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and (8) was characterized. These compounds have proved to be a good starting point for the design of more effective trypanocidal drug candidates.

背景：尽管在全球范围内已经进行了许多研究努力，以发现用于治疗南美锥虫病的新型药物，但硝基咪唑药物苯并尼达唑仍然是控制该病的唯一治疗选择。但是，这种药物在慢性疾病中的疗效下降，长期服用后安全性受到限制，因此有必要寻找新的，更有效和安全的原型。

目的：我们在本文中描述了新型功能化糖肼酰胺（2-10）的合成和针对克氏锥虫的锥虫病形式的锥虫杀灭作用。

方法：通过分子杂交技术在两种强效抗T蛋白之间的应用，设计了这些化合物。Cruzi原型，硝基咪唑衍生物megazol（1）和肉桂基N-酰基hydr衍生物（14）在体外的功效是苯硝唑的两倍。

结果：最具活性的化合物是（Z）-N'-（（E）-3-（4-硝基苯基）-丙烯酰基）-1-甲基-5-硝基-1H-咪唑-2-碳酰肼（6）（ IC50 = 9.50μM）和（Z）-N'-（（（E）-3-（4-羟基苯甲基）-丙烯酰基）-1-甲基-5-硝基-1H-咪唑-2-碳酰肼酰胺（8） （IC50 = 12.85μM），几乎与用作标准药物的苯硝唑（IC50 = 10.26μM）等价。除去相应的N-酰基hydr衍生物（11-13）中亚胺亚基上连接的胺基，导致化合物的效价或活性降低。当对来自瑞士小鼠的哺乳动物细胞进行测试时，对羟基苯基衍生物（8）也具有良好的选择性指数（SI = 32.94）。

结论：表征了新的碳酰肼酰胺衍生物（6）和（8）的有希望的锥虫杀虫特性。这些化合物已被证明是设计更有效的锥虫杀伤候选药物的良好起点。