Back to Search
Start Over
Indirubin Analogues Inhibit Trypanosoma brucei Glycogen Synthase Kinase 3 Short and T. brucei Growth.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 May 24; Vol. 63 (6). Date of Electronic Publication: 2019 May 24 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT). The disease is fatal if it remains untreated, whereas most drug treatments are inadequate due to high toxicity, difficulties in administration, and low central nervous system penetration. T. brucei glycogen synthase kinase 3 short ( Tb GSK3s) is essential for parasite survival and thus represents a potential drug target that could be exploited for HAT treatment. Indirubins, effective leishmanicidals, provide a versatile scaffold for the development of potent GSK3 inhibitors. Herein, we report on the screening of 69 indirubin analogues against T. brucei bloodstream forms. Of these, 32 compounds had potent antitrypanosomal activity (half-maximal effective concentration = 0.050 to 3.2 μM) and good selectivity for the analogues over human HepG2 cells (range, 7.4- to over 641-fold). The majority of analogues were potent inhibitors of Tb GSK3s, and correlation studies for an indirubin subset, namely, the 6-bromosubstituted 3'-oxime bearing an extra bulky substituent on the 3' oxime [(6-BIO-3'-bulky)-substituted indirubins], revealed a positive correlation between kinase inhibition and antitrypanosomal activity. Insights into this indirubin- Tb GSK3s interaction were provided by structure-activity relationship studies. Comparison between 6-BIO-3'-bulky-substituted indirubin-treated parasites and parasites silenced for Tb GSK3s by RNA interference suggested that the above-described compounds may target Tb GSK3s in vivo To further understand the molecular basis of the growth arrest brought about by the inhibition or ablation of Tb GSK3s, we investigated the intracellular localization of Tb GSK3s. Tb GSK3s was present in cytoskeletal structures, including the flagellum and basal body area. Overall, these results give insights into the mode of action of 6-BIO-3'-bulky-substituted indirubins that are promising hits for antitrypanosomal drug discovery.<br /> (Copyright © 2019 American Society for Microbiology.)
- Subjects :
- Animals
Cell Line
Indoles pharmacology
Insecta parasitology
Structure-Activity Relationship
Trypanosomiasis, African drug therapy
Glycogen Synthase Kinase 3 antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Trypanocidal Agents pharmacology
Trypanosoma brucei brucei drug effects
Trypanosoma brucei brucei metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 63
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 30910902
- Full Text :
- https://doi.org/10.1128/AAC.02065-18