Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium.
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, United Kingdom.
Eur J Med Chem. 2019 Feb 15;164:689-705. doi: 10.1016/j.ejmech.2018.12.050. Epub 2018 Dec 21.
The nucleoside antibiotic tubercidin displays strong activity against different target organisms, but it is notoriously toxic to mammalian cells. The effects of tubercidin against T. brucei parasites inspired us to synthesize several C7 substituted analogs for in vitro evaluation in order to find suitable hit compounds. C7 Deazaadenosines substituted with electron-poor phenyl groups were found to have micromolar activity against T. brucei in vitro. Replacement of the phenyl for a pyridine ring gave compound 13, with submicromolar potency and much-attenuated cytotoxicity compared to tubercidin. The veterinary pathogen T. congolense was equally affected by 13in vitro. Transporter studies in T. b. brucei indicated that 13 is taken up efficiently by both the P1 and P2 adenosine transporters, making the occurrence of transporter-related resistance and cross-resistance with diamidine drugs such as diminazene aceturate and pentamidine as well as with melaminophenyl arsenicals unlikely. Evaluation of the in vitro metabolic stability of analog 13 indicated that this analog was significantly metabolized in mouse microsomal fractions, precluding further in vivo evaluation in mouse models of HAT.
核苷抗生素结核菌素对不同的靶标生物显示出很强的活性，但对哺乳动物细胞有很强的毒性。结核菌素对 T. brucei 寄生虫的作用启发我们合成了几种 C7 取代的类似物，以便在体外进行评估，以寻找合适的命中化合物。用缺电子的苯基取代 C7 的脱氧腺苷被发现对 T. brucei 在体外具有微摩尔活性。用吡啶环取代苯基得到化合物 13，与结核菌素相比，其对 T. brucei 的效力低至亚微摩尔，细胞毒性大大降低。兽医病原体 T. congolense 在体外同样受到 13 的影响。在 T. b. brucei 中的转运体研究表明，13 被 P1 和 P2 腺苷转运体有效地摄取，这使得转运体相关的耐药性和与二脒类药物（如延胡索酸盐和戊二脒）以及与苯并胂酸的交叉耐药性不太可能发生。对类似物 13 的体外代谢稳定性评估表明，该类似物在小鼠微粒体部分显著代谢，排除了在 HAT 的小鼠模型中进一步进行体内评估的可能性。
