Search results for "Peptidomimetics"
showing 7 items of 27 documents
Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis
2019
This paper describes an optimization strategy of the highly active vinyl ketone 3 which was recognized as a strong inhibitor of rhodesain of Trypanosoma brucei rhodesiense, endowed with a ksecond v...
Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.
2020
Starting from the reversible rhodesain inhibitors 1 a-c, which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversibl…
Synthesis and biological evaluation of papain-family cathepsin L-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antipr…
2014
Novel papain-family cathepsin L-like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure-activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzod…
Synthesis of novel fluorinated building blocks and α-helix peptidomimetics
2018
At its heart, the present PhD thesis is based on the premise of two important areas in modern organic chemistry: firstly, the development of new methodologies to incorporate fluorine into organic molecules; and secondly, the design and synthesis of small molecules with high therapeutic potential. The work presented in the first three chapters will therefore focus on the incorporation of fluorine into organic molecules and the synthesis of fluorinated building blocks. In each chapter, we aim to obtain biologically relevant small molecules containing fluorine atoms or fluorinated groupings. The introduction of fluorine is a commonly used method in drug discovery to fine-tune the properties of…
Synthesis and Molecular Modeling Studies of Derivatives of a Highly Potent Peptidomimetic Vinyl Ester as Falcipain-2 Inhibitors
2012
Herein we report the synthesis of a set of constrained peptidomimetics endowed with an electrophilic vinyl ester warhead and structurally related to a previously identified lead compound, a potent and irreversible inhibitor of falcipain-2 (FP-2). FP-2 is the main hemoglobinase of the malaria parasite P. falciparum. The new compounds were evaluated for their inhibition against FP-2, and the results were rationalized on the basis of docking experiments. These studies underscore the pivotal role of both the ester function at the P1' site and the trifluoromethyl group of the P3 side chain in determining the correct orientation of the Michael acceptor warhead in the catalytic site, and as a cons…
Synthesis of Hybrid Tripeptide Peptidomimetics Containing Dehydroamino Acid and Aminophosphonic Acid in the Chain and Evaluation of Their Activity to…
2021
Synthesis of a new group of hybrid phosphonodehydropeptides composed of glycyl-(Z)-dehydrophenylalanine and structurally variable aminophosphonates alongside with investigations of their activity towards cathepsin C are presented. Obtained results suggest that the introduction of (Z)- dehydrophenylalanine residue into the short phosphonopeptide chain does induce the ordered conformation. Investigated peptides appeared to act as weak or moderate inhibitors of cathepsin C.
Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors
2016
Novel rhodesain inhibitors were developed by combining an enantiomerically pure 3-bromoisoxazoline warhead with a 1,4-benzodiazepine scaffold as specific recognition moiety. All compounds were proven to inhibit rhodesain with Ki values in the low-micromolar range. Their activity towards rhodesain was found to be coupled to an in vitro antitrypanosomal activity, with IC50 values ranging from the mid-micromolar to a low-micromolar value for the most active rhodesain inhibitor (R,S,S)-3. All compounds showed a good selectivity against the target enzyme since all of them were proven to be poor inhibitors of human cathepsin L. Novel rhodesain inhibitors were developed by combining an enantiomeri…