Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action |
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| Authors: | Dr. Santiago Royo Dr. Santiago Rodríguez Dr. Tanja Schirmeister Jochen Kesselring Dr. Marcel Kaiser Dr. Florenci V. González |
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| Affiliation: | 1. Departament de?Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló (Spain);2. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz (Germany);3. Swiss Tropical and Public Health Institute, Socinstrasse?57, 4051 Basel (Switzerland);4. University of Basel, Petersplatz 1, 4003 Basel (Switzerland) |
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| Abstract: | Dipeptidyl enoates were prepared through a high‐yielding two‐step synthetic route. They have a dipeptidic structure with a 4‐oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S,E)‐ethyl 5‐((S)‐2‐{[(benzyloxy)carbonyl]amino}‐3‐phenylpropanamido)‐7‐methyl‐4‐oxooct‐2‐enoate ( 6 ) was the most potent, with an IC50 value of 16.4 nM and kinact/Ki=1.6×106 M ?1 s?1 against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions. |
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| Keywords: | dipeptidyl enoates inhibitors rhodesain sleeping sickness trypanosomiasis |
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