New<i>Leishmania donovani</i>nucleoside hydrolase inhibitors from Brazilian flora

Nirma, Charlotte; Rangel, Gregorio Torres; Alves, Marina Amaral; Casanova, Livia Marques; Moreira, M. M.; Rodrigues, Luanna Monteiro; Hamerski, Lidilhone; Tinoco, Luzineide W.

doi:10.1039/c9ra02382h

Cited by 12 publications

(14 citation statements)

References 29 publications

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Section: Discussionmentioning

confidence: 99%

“…Inhibitors active against T. vaginalis may also be broadly applicable to other neglected parasites that require nucleoside hydrolase enzymes for their survival such as Leishmania donovani. 37 ■ EXPERIMENTAL SECTION NMR data sets were acquired on a Bruker AvanceIII 500 MHz spectrometer using a BBFO probe. 19 F{ 1 H} NMR spectra were acquired using inverse-gated decoupling with WALTZ-16.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Discovery of Ligand-Efficient Scaffolds for the Design of Novel Trichomonas vaginalis Uridine Nucleoside Ribohydrolase Inhibitors Using Fragment Screening

et al. 2019

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Trichomoniasis is caused by the parasitic protozoan Trichomonas vaginalis. The increasing prevalence of strains resistant to the current 5-nitroimidazole treatments creates the need for novel therapies. T. vaginalis cannot synthesize purine and pyrimidine rings and requires salvage pathway enzymes to obtain them from host nucleosides. The uridine nucleoside ribohydrolase was screened using an 19F NMR-based activity assay against a 2000-compound fragment diversity library. Several series of inhibitors were identified including scaffolds based on acetamides, cyclic ureas or ureas, pyridines, and pyrrolidines. A number of potent singleton compounds were identified, as well. Eighteen compounds with IC50 values of 20 μM or lower were identified, including some with ligand efficiency values of 0.5 or greater. Detergent and jump-dilution counter screens validated all scaffold classes as target-specific, reversible inhibitors. Identified scaffolds differ substantially from 5-nitroimidazoles. Medicinal chemistry using the structure–activity relationship emerging from the fragment hits is being pursued to discover nanomolar inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Discovery of Ligand-Efficient Scaffolds for the Design of Novel Trichomonas vaginalis Uridine Nucleoside Ribohydrolase Inhibitors Using Fragment Screening

et al. 2019

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“…In a recent study, a natural product from Brazilian flora, flavonoids, and proanthocyanidins, with antileishmanial activity screened against LdNH and described as an inhibitor of LdNH [43,177].…”

Section: Nucleoside Hydrolases (Nh Ec 3221)mentioning

confidence: 99%

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Istanbullu¹,

Bayraktar²

2022

Leishmaniasis - General Aspects of a Stigmatized Disease

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The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.

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“…In the same way, that approach has shown good results in the search for inhibitors of nucleoside hydrolase from Leishmania donovani (LdNH). Studies on natural products and fragment based drug discovery integrating the mentioned tools have allowed the identification of potent inhibitors against this target (Alves et al., 2016; Nirma et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

Integration of NMR studies, computational predictions, and in vitro assays in the search of marine diterpenes with antitumor activity

et al. 2021

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Tubulin is the major component of microtubules and plays a crucial role in cell division. Interferences in the dynamics and functioning of tubulin lead to mitotic arrest, cell cycle block, apoptosis, and cell death, making it an effective target for antimitotic drugs used in cancer chemotherapy (Hadfield et al., 2003;Jordan & Wilson, 2004).Tubulin is a protein of 110 kDa that polymerizes to form microtubules, which generally consist of 13 linear protofilaments assembled around a hollow core of 25 nm. The protofilaments, composed of head-to-tail arrays of tubulin dimers (alpha and beta subunits), are arranged in parallel. Microtubules are polar structures with two distinct ends: a fast-growing plus end and a slow-growing minus end (Janke, 2014). The polymerization process is the responsible

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NewLeishmania donovaninucleoside hydrolase inhibitors from Brazilian flora

Abstract: This study presents flavonoids as new inhibitors of the nucleoside hydrolase from Leishmania donovani (LdNH) and the first uncompetitive inhibitor described for LdNH.

Cited by 12 publications

References 29 publications

Discovery of Ligand-Efficient Scaffolds for the Design of Novel Trichomonas vaginalis Uridine Nucleoside Ribohydrolase Inhibitors Using Fragment Screening

Discovery of Ligand-Efficient Scaffolds for the Design of Novel Trichomonas vaginalis Uridine Nucleoside Ribohydrolase Inhibitors Using Fragment Screening

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Integration of NMR studies, computational predictions, and in vitro assays in the search of marine diterpenes with antitumor activity

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