Synthesis, Biochemical Characterization, and Theoretical Studies of Novel β-Keto-enol Pyridine and Furan Derivatives as Potent Antifungal Agents

Said Tighadouini; Smaail Radi; Redouane Benabbes; Moulay Hfid Youssoufi; Sergey Shityakov; Mohamed El Massaoudi; Yann Garcia

doi:10.1021/acsomega.0c02365

Synthesis, Biochemical Characterization, and Theoretical Studies of Novel β-Keto-enol Pyridine and Furan Derivatives as Potent Antifungal Agents

ACS Omega. 2020 Jul 9;5(28):17743-17752. doi: 10.1021/acsomega.0c02365. eCollection 2020 Jul 21.

Authors

Said Tighadouini¹, Smaail Radi², Redouane Benabbes³, Moulay Hfid Youssoufi², Sergey Shityakov⁴, Mohamed El Massaoudi², Yann Garcia⁵

Affiliations

¹ Laboratory of Organic Synthesis, Extraction and Valorization, Faculty of Sciences Ain Chock, Hassan II University, Route d'El Jadida Km 2, BP 5366 Casablanca, Morocco.
² Laboratory of Applied Chemistry & Environment, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco.
³ Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco.
⁴ Department of Bioinformatics, Würzburg University, Am Hubland, 97074 Würzburg, Germany.
⁵ Institute of Condensed Matter and Nanosciences, Molecular Chemistry, Materials and Catalysis (IMCN/MOST), Universite' catholique de Louvain, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium.

Abstract

In the present study, we report the design and synthesis of new derivatives of the β-keto-enol grafted on pyridine and furan moieties (L ₁ -L ₁₁ ). Structures of compounds were fully confirmed by Fourier transform infrared spectroscopy (FT-IR), ¹H NMR, ¹³C NMR, electrospray ionization/liquid chromatography-mass spectrometry (ESI/LC-MS), and elemental analysis. The compounds were screened for antifungal and antibacterial activities (Escherichia coli, Bacillus subtilis, and Micrococcus luteus). In vitro evaluation showed significant fungicidal activity for L ₁ , L ₄ , and L ₅ against fungal strains (Fusarium oxysporum f.sp albedinis) compared to the reference standard. Especially, the exceptional activity has been demonstrated for L ₁ with IC₅₀ = 12.83 μg/mL. This compound and the reference benomyl molecule also showed a correlation between experimental antifungal activity and theoretical predictions by Petra/Osiris/Molinspiration (POM) calculations and molecular coupling against the Fgb1 protein. The highest inhibition of bacterial growth for L ₁ is due to its strongest binding to the target protein. This report may stimulate the further synthesis of examples of this substance class for the development of new drugs.