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

Lourenço, Estela Mariana Guimarães; Di Iório, Juliana Fortes; da Silva, Fernanda; Fialho, Felipe Leonardo Bley; Monteiro, Melquisedeque Mateus; Beatriz, Adilson; Perdomo, Renata Trentin; Barbosa, Euzébio Guimarães; Oses, Jean Pierre; de Arruda, Carla Cardozo Pinto; de Souza Júdice, Wagner Alves; Rafique, Jamal; de Lima, Dênis Pires

doi:10.3390/microorganisms11010225

Open AccessArticle

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

by

Estela Mariana Guimarães Lourenço

¹,

Juliana Fortes Di Iório

²,

Fernanda da Silva

³,

Felipe Leonardo Bley Fialho

¹,

Melquisedeque Mateus Monteiro

⁴,

Adilson Beatriz

¹

,

Renata Trentin Perdomo

⁴,

Euzébio Guimarães Barbosa

⁵,

Jean Pierre Oses

⁶

,

Carla Cardozo Pinto de Arruda

³

,

Wagner Alves de Souza Júdice

^2,*,

Jamal Rafique

^1,7,*

and

Dênis Pires de Lima

^1,*

¹

Laboratory of Synthesis and Transformation of Organic Molecules-SINTMOL, Institute of Chemistry, Universidade Federal de Mato Grosso do Sul, Av. Senador Filinto Muller, Campo Grande 79074-460, MS, Brazil

²

Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes (UMC), Mogi das Cruzes 08780-911, SP, Brazil

³

Laboratório de Parasitologia Humana, Instituto de Biociências, Universidade Federal de Mato Grosso do Sul, Campo Grande 79070-900, MS, Brazil

⁴

Laboratory of Molecular Biology and Cell Culture, School of Pharmaceutical Sciences, Food Technology, and Nutrition, Universidade Federal de Mato Grosso do Sul, Campo Grande 79070-900, MS, Brazil

⁵

Laboratório de Química Farmacêutica Computacional, Departamento de Farmácia, Universidade Federal do Rio Grande do Norte, Natal 59012-570, RN, Brazil

⁶

Laboratório de Neurociências, Instituto de Biociências, Universidade Federal do Rio Grande, Rio Grande 96203-900, RS, Brazil

⁷

Instituto de Química, Universidade Federal de Goiás-UFG, Goiânia 74690-900, GO, Brazil

^*

Authors to whom correspondence should be addressed.

Microorganisms 2023, 11(1), 225; https://doi.org/10.3390/microorganisms11010225

Submission received: 16 November 2022 / Revised: 9 January 2023 / Accepted: 12 January 2023 / Published: 16 January 2023

(This article belongs to the Special Issue Epidemiology of Vector Born Diseases 2.0)

Download

Browse Figures

Versions Notes

Abstract

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.

Keywords: synthesis; leishmaniasis; flavonoids; rCPB; molecular modelling

Share and Cite

MDPI and ACS Style

Lourenço, E.M.G.; Di Iório, J.F.; da Silva, F.; Fialho, F.L.B.; Monteiro, M.M.; Beatriz, A.; Perdomo, R.T.; Barbosa, E.G.; Oses, J.P.; de Arruda, C.C.P.; et al. Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis. Microorganisms 2023, 11, 225. https://doi.org/10.3390/microorganisms11010225

AMA Style

Lourenço EMG, Di Iório JF, da Silva F, Fialho FLB, Monteiro MM, Beatriz A, Perdomo RT, Barbosa EG, Oses JP, de Arruda CCP, et al. Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis. Microorganisms. 2023; 11(1):225. https://doi.org/10.3390/microorganisms11010225

Chicago/Turabian Style

Lourenço, Estela Mariana Guimarães, Juliana Fortes Di Iório, Fernanda da Silva, Felipe Leonardo Bley Fialho, Melquisedeque Mateus Monteiro, Adilson Beatriz, Renata Trentin Perdomo, Euzébio Guimarães Barbosa, Jean Pierre Oses, Carla Cardozo Pinto de Arruda, and et al. 2023. "Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis" Microorganisms 11, no. 1: 225. https://doi.org/10.3390/microorganisms11010225

APA Style

Lourenço, E. M. G., Di Iório, J. F., da Silva, F., Fialho, F. L. B., Monteiro, M. M., Beatriz, A., Perdomo, R. T., Barbosa, E. G., Oses, J. P., de Arruda, C. C. P., de Souza Júdice, W. A., Rafique, J., & de Lima, D. P. (2023). Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis. Microorganisms, 11(1), 225. https://doi.org/10.3390/microorganisms11010225

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

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

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI