Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies

Vičík, Radim; Busemann, Matthias; Gelhaus, Christoph; Stiefl, Nikolaus; Scheiber, Josef; Schmitz, W.; Schulz, F. A.; Mladenović, Milena; Engels, Bernd; Leippe, Matthias; Baumann, Knut; Schirmeister, Tanja

doi:10.1002/cmdc.200600106

Cited by 60 publications

(56 citation statements)

References 38 publications

(51 reference statements)

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“…The difference in antileishmanial activities between epoxide-and aziridine-based inhibitors may be caused by a much higher lipophilicity and, thus, much better cell permeation of compounds 13b and 13e. The low reactivity toward nucleophilic ring opening by thiolates of aziridine-based inhibitors compared to the reactivity of epoxides is the main reason for their weaker activity against the enzymes in protein lysates (11,12,39,40).…”

Section: Discussionmentioning

confidence: 99%

Aziridine-2,3-Dicarboxylate-Based Cysteine Cathepsin Inhibitors Induce Cell Death inLeishmania majorAssociated with Accumulation of Debris in Autophagy-Related Lysosome-Like Vacuoles

Schurigt

Schad

Glowa

et al. 2010

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

Aziridine-2,3-Dicarboxylate-Based Cysteine Cathepsin Inhibitors Induce Cell Death inLeishmania majorAssociated with Accumulation of Debris in Autophagy-Related Lysosome-Like Vacuoles

Schurigt

Schad

Glowa

et al. 2010

Antimicrob Agents Chemother

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“…Activity assays were carried out as described previously (27,34,35). LmCPB2.8 was recombinantly expressed as described previously (36).…”

Section: Methodsmentioning

confidence: 99%

Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases

Schad

Baum²,

Frank³

et al. 2016

Antimicrob Agents Chemother

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L eishmaniasis is one of the 17 neglected tropical diseases (NTDs) assigned by the World Health Organization (WHO). NTDs affect 1 billion people worldwide (1). The primary occurrences are in low-income countries in sub-Saharan Africa, Asia, and Latin America, but the Mediterranean countries of Europe are also concerned (2). Among the NTDs is the group of "most neglected diseases," affecting the poorest, mainly rural areas, including leishmaniases, sleeping sickness (African trypanosomiasis), and Chagas' disease (3). These three NTDs have the highest rates of death. However, the NTD drug discovery pipeline is almost empty, thus leading to a lack of efficient and safe drugs (2, 4). Because of climate warming and tourism, the occurrence of leishmaniasis is also reported in states around the Mediterranean Sea (1).Leishmaniasis is caused by more than 20 species of protozoan parasites belonging to the genus Leishmania. The parasite life cycle is characterized by two morphological stages: extracellular flagellated promastigotes, occurring in the insect vector, and intracellular aflagellated amastigotes, occurring in the mammalian host. The promastigotes are transmitted by an insect bite into the skin of the host, where they are internalized by macrophages, dendritic cells, neutrophils, and fibroblasts and differentiate into amastigotes residing and replicating in parasitophorous vacuoles of these phagocytes. The parasites disseminate through the lymphatic and vascular systems. During the blood meal of an (uninfected) sand fly, amastigotes are transmitted back from the infected mammalian host to the insect vector and differentiate again into promastigotes (5, 6).The clinical outcome of leishmaniasis depends on the complex interactions between the virulence characteristics of the infecting species and the type of immune response of the host. There are three clinical forms: cutaneous, mucocutaneous, and visceral leishmaniases (6).Concerning the treatment of leishmaniasis, it is obvious that new drugs must circumvent the limitations of currently established chemotherapies, i.e., toxicity, long courses of treatment, the frequent need for parenteral administration, high costs in countries where the disease is endemic, and the emergence of resistance. Therefore, it is important not only to test and apply combinations of existing drugs to avoid resistance but also to develop new potential leishmanicidal compounds with alternative mechanisms, as well as vaccination strategies (7,8).Cysteine proteases (CPs) of parasites such as Plasmodium, Trypanosoma, and worms are druggable targets for developing a new promising strategy for chemotherapy based on protease inhi-

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“…Assays with cathepsin L was performed as described previously 18 , Cbz-Phe-Arg-AMC was used as substrate (5 mM).…”

Section: Enzyme Assaysmentioning

confidence: 99%

Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors

Ettari

Previti

Cosconati

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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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 K i values in the low-micromolar range. Their activity towards rhodesain was found to be coupled to an in vitro antitrypanosomal activity, with IC 50 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.

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Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies

Cited by 60 publications

References 38 publications

Aziridine-2,3-Dicarboxylate-Based Cysteine Cathepsin Inhibitors Induce Cell Death inLeishmania majorAssociated with Accumulation of Debris in Autophagy-Related Lysosome-Like Vacuoles

Aziridine-2,3-Dicarboxylate-Based Cysteine Cathepsin Inhibitors Induce Cell Death inLeishmania majorAssociated with Accumulation of Debris in Autophagy-Related Lysosome-Like Vacuoles

Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases

Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors

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