Lien vers Pubmed [PMID] – 30910902
Antimicrob. Agents Chemother. 2019 Mar;
The protozoan parasite () is the causative agent of Human African trypanosomiasis (HAT). The disease is fatal if untreated whereas most drug treatments are inadequate due to high toxicity, difficulties in administration and low CNS penetration. Glycogen Synthase Kinase-3 short (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 developing potent GSK3 inhibitors. Herein, we report the screening of sixty-nine indirubin analogues against bloodstream forms. Of these, thirty-two compounds had a potent anti-trypanosomal activity (EC= 0.050-3.2 μΜ) and good selectivity over human HepG2 cells (ranging from 7.4 to over 641 fold). The majority of analogues were potent inhibitors of GSK3s and correlation studies for an indirubin subset, namely the 6-BIO-3′-bulky substituted indirubins revealed a positive correlation between kinase inhibition and anti-trypanosomal activity. Insights into this indirubin/GSK3s interaction were provided by structure activity relationship studies. Comparison between 6-BIO-3′-bulky substituted indirubins-treated parasites and parasites silenced for GSK3s by RNA interference, suggest that the above compounds may target GSK3s To further understand the molecular basis of growth arrest brought about by the inhibition or ablation of GSK-3s, we investigated the intracellular localization of GSK3s. 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 anti-trypanosomal drug discovery.