3-Phenacylideneoxindoles as a New Class of Antifungal Compounds Against Paracoccidioides Spp.

Abstract

Aims: Considering the need to identify new compounds with antifungal action, the activity of five 3-phenacylideneoxindoles compounds was evaluated. Materials & methods: The compounds were synthesized, and their antifungal activity was elucidated through minimum inhibitory concentration tests and interaction assay with other antifungals. Potential targets of compounds were predicted in silico. Results: 3-phenacylideneoxindoles compounds inhibited fungal growth with minimum inhibitory concentration and minimum fungicidal concentration ranging from 3.05 to 12.26 μM. The compounds demonstrated high selectivity index and presented a synergistic effect with itraconazole. In silico prediction revealed the pentafunctional AROM polypeptide, enolase, superoxide dismutase, catalase and kinases as proteins targets of the compound 4a. Conclusion: The results demonstrate that 3-phenacylideneoxindoles is a potential new class of antifungal compounds for paracoccidioidomycosis treatment.

Plain language summary

Patients affected by paracoccidioidomycosis (PCM) require long-term treatment, which commonly influences their adherence. In addition, only three drugs are in clinical use, which indicates the relevance of research in identifying new drugs for treating PCM. Thus, five drugs were tested in the laboratory to verify whether they could prevent the growth of the fungus without being toxic to humans. In addition, whether these compounds in combination with drugs used to treat PCM could be even more potent was evaluated. All compounds tested efficiently inhibited the growth of Paracoccidioides, the fungus that causes PCM. One drug was identified that, combined with itraconazole, decreased the required dose of both the discovered compound and itraconazole needed to inhibit fungal growth. Using computational tools, this work suggests how the new drug could act against the fungus. The results demonstrate a potential new treatment option, but more studies are needed to confirm the safety of these drugs.

Keywords::

• 3-phenacylideneoxindoles
• antifungal
• paracoccidioidomycosis
• target proteins

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/fmb-2022-0133

Author contributions

Each author has contributed significantly to this work. LC Silva, S Cunha and M Pereira contributed to designing the manuscript and data analysis. RF dos Santos Filho and S Cunha synthesized the compounds, F Terra Martins performed X-ray analysis and LC Silva performed the biological assays. AA de Oliveira performed the computational assays. S Cunha, M Pereira and CM de Almeida Soares contributed to fundraising for the research. All authors contributed to the writing and preparation of the manuscript and approval of the final version of the manuscript.

Acknowledgments

The authors thank Openeye for providing the academic license for the programs used for Molecular Docking.

Financial & competing interests disclosure

This work was performed at Universidade Federal de Goiás and was supported by Ministério da Ciência e Tecnologia/Conselho Nacional de Desenvolvimento Científico e Tecnológico (MCTI/CNPq); Fundo Nacional de Desenvolvimento Científico e Tecnológico (FNDCT); Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG); Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001; CAPES); Financiadora de Estudos e Projetos (FINEP); Programa de Apoio a Núcleos de Excelência (PRONEX); and Instituto Nacional de Ciência e Tecnologia de Estratégias de Interação Patógeno-Hospedeiro (INCT-IPH). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was performed at Universidade Federal de Goiás and was supported by Ministério da Ciência e Tecnologia/Conselho Nacional de Desenvolvimento Científico e Tecnológico (MCTI/CNPq); Fundo Nacional de Desenvolvimento Científico e Tecnológico (FNDCT); Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG); Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001; CAPES); Financiadora de Estudos e Projetos (FINEP); Programa de Apoio a Núcleos de Excelência (PRONEX); and Instituto Nacional de Ciência e Tecnologia de Estratégias de Interação Patógeno-Hospedeiro (INCT-IPH). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.