ArticleACS infectious diseases2015
In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei.
Article in ACS infectious diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Investigating the Antimicrobial Potential of 560 Compounds from the Pandemic Response Box and COVID Box against Resistant Gram-Negative Bacteria.Antibiotics (Basel, Switzerland) · 2024Article
- Multi-target Compounds against Trypanosomatid Parasites andCurrent drug targets · 2024Review
- In Vivo Efficacy of SQ109 againstBiomedicines · 2022Article
- In Vitro and in Vivo Activity of mTOR Kinase and PI3K Inhibitors AgainstMolecules (Basel, Switzerland) · 2020Article
- Novel lead compounds in pre-clinical development against African sleeping sickness.MedChemComm · 2017Review
- Antileishmanial Mechanism of Diamidines Involves Targeting Kinetoplasts.Antimicrobial agents and chemotherapy · 2016Article
Corrections and comments
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Authors and funding
11 authors.
Funding
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.
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Registered trials
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