A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A K
i value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 μM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.
The search for bioactive substances leads to molecules that need to be qualified throughout many complex steps, involving multidisciplinary activities. For antineoplastic molecules, among other classes of candidate drugs, the determination of the biological activity is the core of the whole process with the aim of determining the potency, toxicity and the selectivity index. In this project, in vitro cell-based bioassays of cathepsin inhibitors are going to be performed using prostate cancer cells resistant to chemotherapy (DU 145 and PC-3). Phenotypic studies are going to be used as end-points to observe the cell viability and the perturbation of the cell cycle by means of colorimetric, flow cytometry, coupled with the study of PI3K-Akt-mTOR signaling pathway. Cytotoxic assays are going to be performed in mouse fibroblasts (Balb-c 3T3). As a result, the biological outcome and the cytotoxic profile of the compounds of interest will be addressed.
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