In Vitro and In Vivo Activity of Multi-Target Inhibitors Against Trypanosoma brucei

• Published in: ACS infectious diseases 2015-07, Vol.1 (8), p.388-398
• Main Authors: Yang, Gyongseon, Zhu, Wei, Wang, Yang, Huang, Guozhong, Byun, Sooyoung, Choi, Gahee, Li, Kai, Huang, Zhuoli, Docampo, Roberto, Oldfield, Eric, No, Joo Hwan
• Format: Article
• Language: English
• ISSN: 2373-8227
• DOI: 10.1021/acsinfecdis.5b00068

We tested a series of amidine and related compounds against Trypanosoma brucei . The most active compound was a biphenyldiamidine which had an EC 50 of 7.7 nM against bloodstream form parasites. There was little toxicity against two human cell lines with CC 50 > 100 μM. There was also good in vivo activity in a mouse model of infection with 100% survival at 3 mg/kg i.p. The most potent lead blocked replication of kinetoplast DNA (k-DNA), but not nuclear DNA, in the parasite. Some compounds also inhibited the enzyme farnesyl diphosphate synthase (FPPS) and some were uncouplers of oxidative phosphorylation. We developed a computational model for T. brucei cell growth inhibition (R 2 = 0.76) using DNA ΔT m values for inhibitor binding, combined with T. brucei FPPS IC 50 values. Overall, the results suggest that it may be possible to develop multi-target drug leads against T. brucei that act by inhibiting both k-DNA replication and isoprenoid biosynthesis.