School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
Antimicrobial resistance and Infectious Diseases Laboratory, Harry butler Institute, Murdoch University, 90 South Street, Murdoch, WA 6150, Australia.
ChemMedChem. 2022 Nov 4;17(21):e202200341. doi: 10.1002/cmdc.202200341. Epub 2022 Sep 29.
From four focused compound libraries based on the known anticoccidial agent robenidine, 44 compounds total were synthesised and screened for antigiardial activity. All active compounds were counter-screened for antibiotic and cytotoxic action. Of the analogues examined, 21 displayed IC <5 μM, seven with IC <1.0 μM. Most active were 2,2'-bis{[4-(trifluoromethoxy)phenyl]methylene}carbonimidic dihydrazide hydrochloride (30), 2,2'-bis{[4-(trifluoromethylsulfanyl)phenyl]methylene}carbonimidic dihydrazide hydrochloride (32), and 2,2'-bis[(2-bromo-4,5-dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride (41) with IC =0.2 μM. The maximal observed activity was a 5 h IC value of 0.2 μM for 41. The clinically used metronidazole was inactive at this timepoint at a concentration of 25 μM. Robenidine off-target effects at bacteria and cell line toxicity were removed. Analogue 41 was well tolerated in mice treated orally (100 mg/kg). Following 5 h treatment with 41, no Giardia regrowth was noted after 48 h.
从四个基于已知抗球虫药罗贝林的靶向化合物库中，共合成了 44 种化合物并对其抗贾第虫活性进行了筛选。所有活性化合物均进行了抗生素和细胞毒性的反向筛选。在所检查的类似物中，有 21 种的 IC <5 μM，其中 7 种的 IC <1.0 μM。最活跃的是 2,2'-双{[4-(三氟甲氧基)苯基]亚甲基}碳二亚胺二盐酸盐（30）、2,2'-双{[4-(三氟甲基硫基)苯基]亚甲基}碳二亚胺二盐酸盐（32）和 2,2'-双[(2-溴-4,5-二甲氧基苯基)亚甲基]碳二亚胺二盐酸盐（41），IC =0.2 μM。观察到的最大活性是 41 的 5 h IC 值为 0.2 μM。此时，临床使用的甲硝唑在 25 μM 浓度下无活性。罗贝林对细菌的脱靶效应和细胞系毒性已被消除。类似物 41 在经口给药的小鼠中耐受性良好（100 mg/kg）。用 41 处理 5 小时后，48 小时后未观察到贾第虫再生长。
