title: In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei.
abstract: We tested a series of amidine and related compounds against Trypanosoma brucei. The most active compound was a biphenyldiamidine that 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 multitarget drug leads against T. brucei that act by inhibiting both k-DNA replication and isoprenoid biosynthesis.
authors: Leishmania Research Laboratory, Institut Pasteur Korea , 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.|Interdisciplinary Programs of Functional Genomics, Yonsei University , Seoul 120-749, Republic of Korea.
authors: Gyongseon
authors: G
authors: Yang
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Wei
authors: W
authors: Zhu
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Yang
authors: Y
authors: Wang
authors: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
authors: Guozhong
authors: G
authors: Huang
authors: Leishmania Research Laboratory, Institut Pasteur Korea , 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors: Soo Young
authors: SY
authors: Byun
authors: Leishmania Research Laboratory, Institut Pasteur Korea , 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors: Gahee
authors: G
authors: Choi
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Kai
authors: K
authors: Li
authors: Department of Biochemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Zhuoli
authors: Z
authors: Huang
authors: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
authors: Roberto
authors: R
authors: Docampo
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Eric
authors: E
authors: Oldfield
authors: Leishmania Research Laboratory, Institut Pasteur Korea , 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors: Joo Hwan
authors: JH
authors: No
keywords: computational modeling; farnesyl diphosphate synthase; kinetoplast DNA; proton motive force; sleeping sickness