Dipeptidyl α-fluorovinyl Michael acceptors: Synthesis and activity against cysteine proteases

Steert, Koen; El‐Sayed, Ibrahim; Veken, Pieter Van der; Krishtal, Alisa; Alsenoy, C. Van; Westrop, Gareth D.; Mottram, Jeremy C.; Coombs, Graham H.; Augustyns, Koen; Haemers, Achiel

doi:10.1016/j.bmcl.2007.09.075

Cited by 31 publications

(15 citation statements)

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“…A common feature of most peptide‐derived cysteine protease inhibitors (CPIs) is a so‐called 'warhead': an electrophilic functionality such as a carbonyl group or a Michael acceptor that is attacked by the catalytic cysteine thiolate in the active site (Figure 1). The choice of warhead type, either those that irreversibly bind, as for Michael acceptors,17 or which are reversibly reactive, such as ketones, is arguably often in favor of the latter reversible types. These might be expected to possess better safety profiles regarding their potential application as drugs for treating parasitic infections.…”

Section: Introductionmentioning

confidence: 99%

α‐Ketoheterocycles as Inhibitors of Leishmania mexicana Cysteine Protease CPB

et al. 2010

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Cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles in the biology of parasites. Inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas disease, and leishmaniasis. Inspired by the in vivo antiparasitic activity of the vinylsulfone-based cysteine protease inhibitors, a series of α-ketoheterocycles were developed as reversible inhibitors of a recombinant L. mexicana cysteine protease, CPB2.8. Three isoxazoles and especially one oxadiazole compound are potent reversible inhibitors of CPB2.8; however, in vitro whole-organism screening against a panel of protozoan parasites did not fully correlate with the observed inhibition of the cysteine protease.

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Section: Introductionmentioning

confidence: 99%

α‐Ketoheterocycles as Inhibitors of Leishmania mexicana Cysteine Protease CPB

et al. 2010

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“…The first study was conducted in Brazil and described synthesis of novel dipeptidyl alpha-fluoro-vinyl sulfones. The results showed that addition of Michael receptor to synthesized compounds revealed satisfactory inhibition of L. mexicana CP [32] . The second German study reported that diastereomeric E-configured vinylogous dipeptide esters were the most active inhibitors against the major CPs of P. falciparum (falcipain) and T. brucei (rhodesain).…”

Section: Cysteine Proteinase Inhibitors (Cpis)mentioning

confidence: 98%

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

Abaza

2019

Parasitologists United Journal

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Cysteine proteinases (CPs) Being essential for parasite survival, CPs are investigated for development of vaccine candidates and/or novel drugs in protozoal diseases with high mortality and morbidity rates such as malignant malaria, African sleeping sickness and Chagas' disease, as well as neglected tropical diseases such as visceral leishmaniasis, toxoplasmosis, extraintestinal amoebiasis and cryptosporidiosis. Caffrey and Steverding [1] , in their review, introduced a unified nomenclature for kinetoplastid cathepsins (CATHs) and discussed their expressions in different developmental stages, essential functions, as well as genomic organization. They also discussed the feasibility of application of these CPs in development of vaccine candidates. Recent evolution in molecular technology and bioinformatics enable researchers to localize and analyze the biologic cellular functions of several expressed CPs. In addition, CPs abundance in parasites compared to their mammalian hosts attract scientists to search for specific CP inhibitors for development of safe chemotherapeutic agents without host adverse side effects. In this regard, Caffrey et al., [2] reviewed CPs of clan CA, family C1 in kinetoplastids and discussed their biochemical and genetic diversity as well as their genomics in relation to stage-specificity and expression control. The reviewers aimed at utilizing literature date as first step to achieve development of novel drugs and/or vaccine candidates to control visceral leishmaniasis, African sleeping sickness and Chagas' disease. On the other hand, complete genome sequences of three human pathogenic trypanosomatids, T. brucei, T. cruzi and Leishmania spp. followed by in silico analyses allowed the researchers to identify and assign 23, 40 and 33 genes involved in calpains (CALPs) expression in different stages of T. brucei, T. cruzi and L. braziliensis, respectively. In a review article published two years later, the reviewers discussed the biochemical and biological aspects of CALPs expressed in these trypanosomatids. They focused on the fact that knowing the genome sequences in drug-resistant and-sensitive strains will allow the investigators to investigate the inhibitory efficiency of several CALP inhibitors [3]. Furthermore, CPs were utilized as diagnostic markers. In 2005, Brazilian investigators described SDS-PAGE for in situ detection of CP activity using its specific CP inhibitor to differentiate between flagellates isolated from insects and plants [4]. In the same year, a group of scientists from UK employed genomic analysis to identify genes encoding CALPs in three human kinetoplastids; L. major, T. cruzi, and T. brucei.

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“…These include peptide‐based inhibitors bearing an electrophilic warhead that covalently traps the catalytic thiolate such as dipeptidyl vinyl sulfone 1 , dipeptidyl α‐ketoheterocycles 2 and aziridinyl peptides (e.g. 3 ), semicarbazone 4 , thiosemicarbazones 5 , triazine nitrile 6 , natural compounds (e.g. morelloflavones 7 ), and a decorated fused benzo[ b ]thiophene inhibitor 8 acting through a time‐dependent bimodal mechanism of action (Figure ) …”

Section: Introductionmentioning

confidence: 99%

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

et al. 2018

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Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2-substituted-1H-benzo[d]imidazole derivatives (9a-d) showing affinity in the submicromolar range (K = 0.15-0.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of Leishmania infantum with the best result being obtained with derivative 9d (IC = 6.8 μM), although with some degree of cytotoxicity (CC = 8.0 μM on PMM and CC = 32.0 μM on MCR-5). In silico molecular docking studies and ADME-Tox properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives.

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Dipeptidyl α-fluorovinyl Michael acceptors: Synthesis and activity against cysteine proteases

Cited by 31 publications

References 20 publications

α‐Ketoheterocycles as Inhibitors of Leishmania mexicana Cysteine Protease CPB

α‐Ketoheterocycles as Inhibitors of Leishmania mexicana Cysteine Protease CPB

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

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