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New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8

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JournalEuropean Journal of Medicinal Chemistry
DateAccepted/In press - 6 Jul 2018
DateE-pub ahead of print - 9 Jul 2018
DatePublished (current) - 5 Aug 2018
Pages (from-to)587-597
Early online date9/07/18
Original languageEnglish


In the present work a series of aziridine-2,3-dicarboxylate inhibitors of papain-like cysteine proteases was designed, synthesized and tested. The compounds displayed selectivity for the parasitic protozoon Leishmania mexicana cathepsin L-like cysteine protease LmCPB2.8. The computational methods of homology modelling and molecular docking predicted some significant differences in the S2 pocket of LmCPB2.8 and cruzain, a related enzyme from Trypanosoma cruzi. Due to the presence of Tyr209 in LmCPB2.8 rather than Glu208 in cruzain sterically demanding, lipophilic ester groups (inhibitor 7d, 9d, 12d and 14d) are predicted to occupy the S2 pocket of the Leishmania protease, but do not form favorable interactions in cruzain, which is in common with our experimental results. Further, inhibitor 18 bearing a free carboxylic acid attached to the aziridine moiety showed a time-dependent inhibition of LmCPB2.8 (Ki = 0.41 μM; k2nd = 190,569 M−1 min−1). Docking results suggested a strong ionic interaction with the positively charged His163 of the active site. Biological and theoretical data confirm that the novel selective aziridine-based inhibitors are promising candidates for further optimization as LmCPB2.8 inhibitors.

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© 2018 Elsevier Masson SAS. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy.

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