Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense

作者：Daunes Sylvie; Yardley Vanessa; Croft Simon L; D'Silva Claudius^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(4): 1329-1340.

DOI：10.1016/j.bmc.2016.12.016

• Trypanosoma brucei rhodesiense
• Trypanosoma cruzi
• Leishmania donovani
• Antiprotozoal peptides
• Glutathione derivatives
• Membrane rafts
• Flagellar pocket
• Endocytosis
• MPRA receptor

A new series of N-substituted S-(2,4-dinitrophenyl)glutathione dibutyl diesters were synthesized to improve in vitro anti-protozoal activity against the pathogenic parasites Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. The results obtained indicate that N-substituents enhance the inhibitory properties of glutathione diesters whilst showing reduced toxicity against KB cells as in the cases of compounds 5, 9, 10, 16, 18 and 19. We suggest that the interaction of N-substituted S-(2,4-dinitrophenyl) glutathione dibutyl diesters with T. b. brucei occurs mainly by weak hydrophobic interactions such as London and van der Waals forces. A QSAR study indicated that the inhibitory activity of the peptide is associated negatively with the average number of C atoms, N-C and positively to S-ZX, the ZX shadow a geometric descriptor related to molecular size and orientation of the compound. HPLC-UV studies in conjunction with optical microscopy indicate that the observed selectivity of inhibition of these compounds against bloodstream form T. b. brucei parasites in comparison to L. donovani under the same conditions is due to intracellular uptake via endocytosis in the flagellar pocket.

• 出版日期2017-2-15