Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors

Avelar, Leandro A. Alves; Camilo, Christian D; Albuquerque, Sérgio de; Fernandes, William Borges; Gonçalez, Cristiana; Kenny, Peter W.; Leitão, Andrei; McKerrow, James H.; Montanari, Carlos Alberto; Orozco, Erika Vanessa Meñaca; Ribeiro, Jean Francisco Rosa; Rocha, Jansle Vieira; Rosini, Fabiana; Saidel, Marta Érica

doi:10.1371/journal.pntd.0003916

Cited by 71 publications

(100 citation statements)

References 55 publications

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“…In this case, attack of the thiol group present in the active site of the enzyme interacts with the nitrile group, which results in a thioimidate intermediate (Scheme b). Dipeptidyl nitriles are known to be reversible inhibitors of cruzain . Therefore, the nitrile group of the tyrphostins can, in principle, be a point of interaction with cruzain.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

et al. 2018

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Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)-(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine-phosphorylation-regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

et al. 2018

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“…Synthesis and characterization of compounds 6 , 9 and 11 have been already published elsewhere [13].…”

Section: Methodsmentioning

confidence: 99%

“…The structure of Cz is closely related to those of mammalian CPs (CatL, CatK and CatS). Three-dimensional (3D) structures of Cz a variety of ligands have already been resolved [13], enabling the applicability of target-based molecular design to find Cz-inhibiting P1, P2, and P3 positions of dipeptidyl nitrile ligands with the respective subsites of the enzyme (S1, S2, S3) and the trypanocidal activities of such inhibitors [14]. In this study, we designed a new, structurally expanded series of 26 Cz-inhibiting dipeptidyl nitriles, in particular by leveraging the P1-S1/S1′ interactions.…”

Section: Introductionmentioning

confidence: 99%

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

Cianni¹,

Lemke²,

Gilberg³

et al. 2019

Preprint

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26The cysteine protease cruzipain is considered to be a validated target for therapeutic 27 intervention in the treatment of Chagas disease. A series of 26 new compounds 28 waswere designed, synthesized, and tested against the recombinant cruzain (Cz) to 29 map its S1/S1´ subsites. The same series was evaluated on a panel of four human 30 cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which 31 is a potential target for the treatment of cutaneous leishmaniasis. The synthesized 32 compounds are dipeptidyl nitriles designed based on the most promising 33 combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building 34 blocks). Eight compounds exhibited a K i smaller than 20.0 nM for Cz, whereas three 35 compounds met these criteria for LmCPB. The three inhibitors had an EC 50 value of 36 ca. 4 μM, thus being equipotent to benznidazole according to the anti-trypanosomal 37 effects. Our mapping approach and the respective structure-activity relationships 38 provide insights into the specific ligand-target interactions for therapeutically relevant 39 cysteine proteases. 40 41 Author Summary 42 43 Despite many achievements in identifying novel agents for the treatment of tropical 44 and neglected diseases, further research continues to be of fundamental importance.45 Our research groups have been using the cruzipain cysteine protease in its 46 recombinant form, cruzain (Cz), to identify new trypanocidal agents. Considering the 47 50 different disease states. Thus, the inhibitors were also tested against cathepsins B, 51 L, K, and S. Our results demonstrate that inhibition of these cysteine proteases can 52 be achieved by appropriate structural modifications of dipeptidyl nitriles. It was also 53 possible to identify trypanocidal agents, equipotent to benznidazole, the current drug 54 of choice used for the treatment of Chagas disease. 55 56 57 Chagas disease, aka American trypanosomiasis, is a serious health and social 58 problem in Latin America and new non-endemic areas such as Japan, East Europe, 59 and the USA. Chagas disease has an annual incidence of 30,000 new cases and 60 14,000 deaths per year. In addition, more than 70,000 million people living in areas 61 where they are at risk of contracting the disease [1]. 62 The etiological agent, the protozoa parasite Trypanosoma cruzi (T. cruzi), is 63 transmitted by blood-sucking reduviid bugs of the subfamily Triatominae [2]. The only 64 two existing drugs in the market, benznidazole and nifurtimox, show strong side 65 effects and inefficiency in the chronic stage of the disease [3,4]. New safe and 66 efficacious drugs are therefore required to address with these still unmet medical 67 needs. Initiatives such as the one launched by the Drugs for Neglected Diseases 68 (DNDi) have led to worldwide collaborative efforts to discover new therapeutic 69 targets [5]. Cruzain (Cz), a recombinant form of the enzyme cruzipain (EC 3.4.22.51) 70 [6], is the most abundant cysteine protease (CP) present in the parasite and 7...

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“…The assay was carried out using a FluoReporter lacZ/Galactosidase Quantitative Kit (Life Technologies) [22]. Briefly, LLC-MK2 cells were cultured in 96-well plates (10 4 cells/mL).…”

Section: Evaluation Of the Activity On Amastigote Formmentioning

confidence: 99%

Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs

Rettondin

Carneiro

Gonçalves

et al. 2016

European Journal of Medicinal Chemistry

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Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors

Cited by 71 publications

References 55 publications

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs

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