Development of novel dipeptide nitriles as inhibitors of rhodesain of Trypanosoma brucei rhodesiense
| Autor: | Carla Di Chio, Santo Previti, Giorgio Amendola, Rahul Ravichandran, Annika Wagner, Sandro Cosconati, Ute A. Hellmich, Tanja Schirmeister, Maria Zappalà, Roberta Ettari |
|---|---|
| Přispěvatelé: | Di Chio, C., Previti, S., Amendola, G., Ravichandran, R., Wagner, A., Cosconati, S., Hellmich, U. A., Schirmeister, T., Zappala, M., Ettari, R. |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Trypanosoma brucei rhodesiense
Pharmacology Dipeptide nitrile Organic Chemistry Dipeptides General Medicine Cysteine Proteinase Inhibitors Antitrypanosomal agent Trypanocidal Agents Cysteine Endopeptidases Structure-Activity Relationship Docking studie Nitriles Drug Discovery Rhodesain inhibitors Cysteine protease |
| Popis: | In this paper, we developed a new series of dipeptide nitriles that were demonstrated to be reversible rhodesain inhibitors at nanomolar level, with EC50 values against cultured T. b. brucei in the micromolar range. We also proved that our dipeptide nitriles directly bind to the active site of rhodesain acting as competitive inhibitors. Within the most interesting compounds, the dipeptide nitrile 2b showed the highest binding affinity towards rhodesain (Ki = 16 nM) coupled with a good antiparasitic activity (EC50 = 14.1 μM). Moreover, for the dipeptide nitrile 3e, which showed a Ki = 122 nM towards the trypanosomal protease, we obtained the highest antiparasitic activity (EC50 = 8.8 μM). Thus, given the obtained results both compounds could certainly represent new lead compounds for the discovery of new drugs to treat Human African Trypanosomiasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|