背景:目前治疗查加斯病(CD)的方法包括苯并咪唑和硝呋替莫,具有有限的功效并引起许多副作用。三唑类药物是新的CD治疗的候选药物,因为它们能够通过抑制麦角固醇合成来消除克氏虫寄生虫,从而破坏寄生虫的细胞膜。
方法:针对β-半乳糖苷酶转染的Tulahuen菌株,在体外筛选了含有三唑核心的激酶抑制剂SRPIN340的11种合成类似物(化合物6A-6K),并计算了它们的IC50、CC50和选择性指数(SI)。SI>50的化合物通过快速测试在感染T.cruziY菌株的小鼠中进一步评估。
结果:八种化合物在体外具有活性,IC50值为0.5-10.5µg/mL。最活跃的化合物,6E和6H,SI值分别为125.2和69.6。这些化合物还显示出体内活性,导致剂量为10、50和250mg/kg/天的寄生虫血症减少。在50和250mg/kg/天的剂量下,与未经感染的动物相比,寄生虫血症显着降低,6E和6H的影响没有显著差异。
结论:本研究确定了两种用于CD化疗的新的有希望的化合物,并证实了它们对T.cruzi的活性。
BACKGROUND: The current treatments for Chagas disease (CD) include benznidazole and nifurtimox, which have limited efficacy and cause numerous side effects. Triazoles are candidates for new CD treatments due to their ability to eliminate T. cruzi parasites by inhibiting ergosterol synthesis, thereby damaging the cell membranes of the parasite.
METHODS: Eleven synthetic analogs of the kinase inhibitor SRPIN340 containing a triazole core (compounds 6A-6K) were screened in vitro against the Tulahuen strain transfected with β-galactosidase, and their IC50, CC50, and selectivity indexes (SI) were calculated. Compounds with an SI > 50 were further evaluated in mice infected with the T. cruzi Y strain by rapid testing.
RESULTS: Eight compounds were active in vitro with IC50 values ranging from 0.5-10.5 µg/mL. The most active compounds, 6E and 6H, had SI values of 125.2 and 69.6, respectively. These compounds also showed in vivo activity, leading to a reduction in parasitemia at doses of 10, 50, and 250 mg/kg/day. At doses of 50 and 250 mg/kg/day, parasitemia was significantly reduced compared to infected untreated animals, with no significant differences between the effects of 6E and 6H.
CONCLUSIONS: This study identified two new promising compounds for CD chemotherapy and confirmed their activity against T. cruzi.