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Discovery of Synthetic Imine-Chalcones Targeting Mayaro Virus Replication
Leonardo Dos Santos Corrêa-Amorim1,2, Natasha Cristina da Rocha1, Geicy Kelly P Barboza3
1Laboratório de Virologia Molecular e Biotecnologia Marinha, Programa de Pós-Graduação em Ciências e Biotecnologia, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói 24210-201, RJ, Brazil.
Abstract:
Mayaro virus (MAYV) is an arthritogenic alphavirus transmitted by mosquitoes and is the causative agent of Mayaro fever. This disease is associated with symptoms such as arthralgia and myalgia, which may persist for months or even years. Currently, no vaccine or specific antiviral therapy is available. This study aimed to assess the antiviral activity of synthetic imine-chalcone derivatives (1a-1d) against MAYV replication in Vero cells and predict their pharmacokinetic and toxicological properties. All compounds presented low cytotoxicity, with CC50 values ranging from 249.92 µM to >1000 µM. Additionally, the derivatives showed good antiviral activity, with compound 1a being the most potent (EC50 = 12.15 μM; SI = 31.47), and 1b being the most selective (EC50 = 16.92 μM; SI > 59.10). Mechanistic assays revealed that compounds 1a and 1b primarily inhibit early events in the MAYV life cycle, such as viral adsorption (1a: 51.53%; 1b: 59.35%) and entry (1a: 71.26%; 1b: 54.21%). Compound 1b also impaired virus egress, while none of the compounds exhibited strong virucidal activity. Finally, in silico ADMET predictions suggested favorable pharmacokinetic and toxicological parameters for compounds 1a and 1b. Overall, our work demonstrated for the first time the activity and safety of imine-chalcones against MAYV.
Insights
New imine-chalcone derivatives show promise as Mayaro virus (MAYV) antivirals. Compounds 1a and 1b effectively inhibit viral replication and exhibit favorable safety profiles, offering potential for Mayaro fever treatment.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- Mayaro virus (MAYV) causes Mayaro fever, characterized by persistent arthralgia and myalgia.
- Current treatment options for Mayaro fever are limited, with no available vaccines or specific antiviral therapies.
Purpose of the Study:
- To evaluate the antiviral activity of synthetic imine-chalcone derivatives (1a-1d) against MAYV replication.
- To predict the pharmacokinetic and toxicological properties of these compounds.
Main Methods:
- Assessing antiviral activity in Vero cells.
- Determining cytotoxicity (CC50) and selectivity index (SI).
- Conducting mechanistic assays to elucidate the mode of action (adsorption, entry, egress).
- Utilizing in silico ADMET predictions for pharmacokinetic and toxicological profiling.
Main Results:
- All imine-chalcone derivatives exhibited low cytotoxicity (CC50 > 249.92 µM).
- Compounds 1a and 1b demonstrated significant antiviral activity (EC50 = 12.15 µM and 16.92 µM, respectively).
- Mechanistic studies indicated inhibition of MAYV adsorption and entry by compounds 1a and 1b; compound 1b also affected virus egress.
- In silico analysis predicted favorable ADMET properties for compounds 1a and 1b.
Conclusions:
- Imine-chalcone derivatives, particularly compounds 1a and 1b, possess significant antiviral activity against MAYV.
- These compounds demonstrate a promising safety profile and favorable pharmacokinetic predictions.
- This study highlights the potential of imine-chalcones as a novel therapeutic strategy for Mayaro fever.
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