Multitarget 2′-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities

Kamecki, Fabiola; Knez, Damijan; Carvalho, Diego B.; Marcucci, Carolina; Rademacher, Marina; Higgs, Josefina; Žakelj, Simon; Marcos, Alejandra; Pinto, Felicitas de Tezanos; Abin-Carriquiry, Juan Andrés; Gobec, Stanislav; Colettis, Natalia Claudia; Marder, Mariel

doi:10.1016/j.neuropharm.2021.108837

Cited by 8 publications

(6 citation statements)

References 85 publications

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“…Furthermore, compounds f12a–f13c presented an OH group signal at 9.60–9.30 ppm, indicating the loss of 2-hydroxy from the starting material (chalcone), classically observed with a larger chemical shift due to the intramolecular H bond with the carbonyl group. The NMR data were compared with the literature, and the structures of the synthesised compounds were confirmed [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. The spectra are available in the Supplementary Material .…”

Section: Resultsmentioning

confidence: 99%

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

et al. 2023

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Leishmaniasis is a neglected tropical disease, affecting more than 350 million people globally. However, there is currently no vaccine available against human leishmaniasis, and current treatment is hampered by high cost, side-effects, and painful administration routes. It has become a United Nations goal to end leishmaniasis epidemics by 2030, and multitarget drug strategy emerges as a promising alternative. Among the multitarget compounds, flavonoids are a renowned class of natural products, and a structurally diverse library can be prepared through organic synthesis, which can be tested for biological effectiveness. In this study, we synthesised 17 flavonoid analogues using a scalable, easy-to-reproduce, and inexpensive method. All synthesised compounds presented an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y enzymes, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b were found to be effective against all isoforms. Furthermore, their intermolecular interactions were also investigated through a molecular modelling study. These compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. These results are pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Moreover, compounds have been shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases.

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Section: Resultsmentioning

confidence: 99%

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

et al. 2023

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“…All synthetic flavonol and chalcone derivatives were obtained following the same procedure described by Lourenço et al (2023) . The NMR data, retention factor ( Rf ) values, and melting points were compared with the literature, and the structures of the synthesized compounds were confirmed. − Spectroscopic data are available in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Investigation of the Potential Targets behind the Promising and Highly Selective Antileishmanial Action of Synthetic Flavonoid Derivatives

Lourenço,

da Silva,

das Neves

et al. 2023

ACS Infect. Dis.

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Leishmaniases are among the neglected tropical diseases that still cause devastating health, social, and economic consequences to more than 350 million people worldwide. Despite efforts to combat these vector-borne diseases, their incidence does not decrease. Meanwhile, current antileishmanial drugs are old and highly toxic, and safer presentations are unaffordable to the most severely affected human populations. In a previous study by our research group, we synthesized 17 flavonoid derivatives that demonstrated impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y. These cysteine proteases are highly expressed in the amastigote stage, the target form of the parasite. However, although these compounds have been already described in the literature, until now, the amastigote effect of any of these molecules has not been proven. In this work, we aimed to deeply analyze the antileishmanial action of this set of synthetic flavonoid derivatives by correlating their ability to inhibit cysteine proteases with the action against the parasite. Among all the synthesized flavonoid derivatives, 11 of them showed high activity against amastigotes of Leishmania amazonensis, also providing safety to mammalian host cells. Furthermore, the high production of nitric oxide by infected cells treated with the most active cysteine protease B (CPB) inhibitors confirms a potential immunomodulatory response of macrophages. Besides, considering flavonoids as multitarget drugs, we also investigated other potential antileishmanial mechanisms. The most active compounds were selected to investigate another potential biological pathway behind their antileishmanial action using flow cytometry analysis. The results confirmed an oxidative stress after 48 h of treatment. These data represent an important step toward the validation of CPB as an antileishmanial target, as well as aiding in new drug discovery studies based on this protease.

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“…Furthermore, compounds f12a-f13c presented a signal of the OH group in 9.60 -9.30, indicating the loss of 2-hydroxy from their starting material (chalcone), classically observed in larger chemical shift due to the intramolecular H bond with the carbonyl group. The NMR data was compared with those of the literature and the structures of the synthesized compounds were confirmed [25][26][27][28][29][30][31][32][33][34][35][36][37]. The spectra are available in the Supplementary material.…”

Section: Chemistrymentioning

confidence: 96%

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

Lourenço¹,

Iório²,

Silva³

et al. 2022

Preprint

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Leishmaniasis is a neglected tropical disease and affects more than 350 million people worldwide. However, there are no vaccines for humans, and current treatment is hampered due to its high cost, numerous side effects, and painful administration routes. Ending its epidemics by 2030 has become a United Nations goal, and the multitarget drug strategy emerges as a promising alternative. Flavonoids are an example of multitarget compounds and organic synthesis represents a tool to obtain high yields of these molecules. In our study, we synthesized 17 flavonoid analogs using a scalable, easy-to-reproduce, and inexpensive method. All compounds demonstrated an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b stood out as effective against all isoforms and intermolecular interactions were investigated through a molecular modeling study. The compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. The results were pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Furthermore, compounds have shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases.

show abstract

Multitarget 2′-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities

Cited by 8 publications

References 85 publications

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

Investigation of the Potential Targets behind the Promising and Highly Selective Antileishmanial Action of Synthetic Flavonoid Derivatives

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

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