Antifungal Efficacy of Imidazo[1,2-a]Pyrazine-Based Thiosemicarbazones and Thiazolidinediones Against Sporothrix Species

Abstract

Aim: To evaluate antifungal potential of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids based on thiosemicarbazones and thiazolidinediones against pathogenic Sporothrix species. Methods: Antifungal activity of nine compounds were assessed by broth microdilution. Interactions between active compounds and itraconazole were evaluated by the checkerboard assay using non-wild-type isolates. Cytotoxicity of the compounds was determined. Results: Four C-3 substituted analogs showed antifungal activity, unrelated to thiosemicarbazone or thiazolidinedione functions. Synergistic interactions between the four compounds and itraconazole, and low toxicity on mouse fibroblast cells were observed. Activity of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids against Sporothrix depended on the substitution on the imidazopyrazine ring. Conclusion: Antifungal potential, overcoming itraconazole resistance and low toxicity indicate the possible use of that series of compounds in a therapeutic alternative for treatment of sporotrichosis.

Keywords::

• 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids
• itraconazole
• Sporothrix
• synergism

Author contributions

RG Lima-Neto: substantial contributions in the conception and design of the work; acquisition, analysis and interpretation of data; drafting and revision for intellectual content of the the manuscript; final approval of the version to be published; and accountability for all aspects of the work to ensure that questions related to its accuracy or integrity are appropriately investigated and solved. MS Araújo Neta, CAT Valeriano, RP Neves, AM Lacerda, CE Ferraz and CP Inácio: acquisition, analysis and interpretation of data; final approval of the version to be published. P Le Pape and I Ourliac-Garnier: substantial contributions to the conception and design of the work; drafting and revision for intellectual content of the the manuscript; final approval of the version to be published. AR Faria, TG Silva and VRA Pereira: acquisition, analysis and interpretation of data; final approval of the version to be published. P Marchand: substantial contributions in the conception and design of the work; acquisition, analysis and interpretation of data; drafting and revision for intellectual content of the the manuscript; final approval of the version to be published; accountability for all aspects of the work to ensure that questions related to its accuracy or integrity are appropriately investigated and solved.

Acknowledgments

The authors thank the Dermatological Service at the Hospital of Clinics at the Federal University of Pernambuco and the reference health service in sporotrichosis in the state of Pernambuco for follow-up of the patients and providing their data.

Financial & competing interests disclosure

This work was supported by Grant CAPES-COFECUB international cooperation process 59/2014. It was partially funded by the Support Fundation in Science and Technology of the State of Pernambuco (FACEPE/PPSUS 06/2020 grant APQ-0295-2.12/20, and FACEPE 17/2021 grant APQ-1061-4.01/21). RG de Lima-Neto is a fellow researcher by the CNPq/MCTI/Brazil (grant 310414/2022-9). 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.

Ethical conduct of research

This study was approved by the Research Ethical Committee for Human Research of the Center for Health Sciences of the Federal University of Pernambuco under process 2.199.596.

Additional information

Funding

This work was supported by Grant CAPES-COFECUB international cooperation process 59/2014. It was partially funded by the Support Fundation in Science and Technology of the State of Pernambuco (FACEPE/PPSUS 06/2020 grant APQ-0295-2.12/20, and FACEPE 17/2021 grant APQ-1061-4.01/21). RG de Lima-Neto is a fellow researcher by the CNPq/MCTI/Brazil (grant 310414/2022-9). 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.