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

doi:10.1021/acsomega.0c02365

. 2020 Jul 9;5(28):17743-17752.

doi: 10.1021/acsomega.0c02365. eCollection 2020 Jul 21.

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

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.

PMID: 32715261
PMCID: PMC7377641
DOI: 10.1021/acsomega.0c02365

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

Said Tighadouini et al. ACS Omega. 2020.

. 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.

PMID: 32715261
PMCID: PMC7377641
DOI: 10.1021/acsomega.0c02365

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

**Figure 1**
Molecular structures of some drugs containing keto-enol functionality.

**Scheme 1. Synthetic Route for the Compounds L₁–L₁₁**

**Figure 2**
R substituent for L₁, L₄, and L₅.

**Figure 3**
Antibacterial and antifungal pharmacophore sites for L₁.

**Figure 4**
Binding conformations predicted from the ADVina runs for benomyl (a), L₁ (b), and L₄ (c) bound to β-tubulin of *F. oxysporum*. The protein (**Fgb1**) binding site is shown by the molecular surface and colored according to the protein atomic composition. All protein residues are drawn as ball-and-stick models. Hydrogen bonds are visualized as dashed lines. The ligand molecules are depicted in sticks, and hydrogen atoms were removed to enhance clarity.

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References

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[1] Fisher M. C.; Henk D. A.; Briggs C. J.; Brownstein J. S.; Madoff L. C.; McCraw S. L.; Gurr S. L. Emerging fungal threats to animal, plant and ecosystem health. Nature 2012, 484, 186–194. 10.1038/nature10947. - DOI - PMC - PubMed

[2] Fisher M. C.; Henk D. A.; Briggs C. J.; Brownstein J. S.; Madoff L. C.; McCraw S. L.; Gurr S. L. Emerging fungal threats to animal, plant and ecosystem health. Nature 2012, 484, 186–194. 10.1038/nature10947. - DOI - PMC - PubMed

[3] Nicola A. M.; Albuquerque P.; Paes H. C.; Fernandes L.; Costa F. F.; Kioshima E. S.; Abadio A. K. R.; Bocca A. L.; Felipe M. S. Antifungal drugs: new insights in research & development. Pharmacol. Ther. 2019, 195, 21–38. 10.1016/j.pharmthera.2018.10.008. - DOI - PubMed

[4] Nicola A. M.; Albuquerque P.; Paes H. C.; Fernandes L.; Costa F. F.; Kioshima E. S.; Abadio A. K. R.; Bocca A. L.; Felipe M. S. Antifungal drugs: new insights in research & development. Pharmacol. Ther. 2019, 195, 21–38. 10.1016/j.pharmthera.2018.10.008. - DOI - PubMed

[5] Brown G. D.; Denning D. W.; Gow N. A.; Levitz S. M.; Netea M. G.; White T. C. Hidden killers: human fungal infections. Sci. Transl. Med. 2012, 4, 165rv1310.1126/scitranslmed.3004404. - DOI - PubMed

[6] Brown G. D.; Denning D. W.; Gow N. A.; Levitz S. M.; Netea M. G.; White T. C. Hidden killers: human fungal infections. Sci. Transl. Med. 2012, 4, 165rv1310.1126/scitranslmed.3004404. - DOI - PubMed

[7] Xie G. H.; Fang X. M.; Fang Q.; Wu X. M.; Jin Y. H.; Wang J. L.; Guo Q. L.; Gu M. N.; Xu Q. P.; Wang D. X.; Yao S. L.; Yuan S. Y.; Du Z. H.; Sun Y. B.; Wang H. H.; Wu S. J.; Cheng B. L. Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients. Crit. Care 2008, 12, R5.10.1186/cc6766. - DOI - PMC - PubMed

[8] Xie G. H.; Fang X. M.; Fang Q.; Wu X. M.; Jin Y. H.; Wang J. L.; Guo Q. L.; Gu M. N.; Xu Q. P.; Wang D. X.; Yao S. L.; Yuan S. Y.; Du Z. H.; Sun Y. B.; Wang H. H.; Wu S. J.; Cheng B. L. Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients. Crit. Care 2008, 12, R5.10.1186/cc6766. - DOI - PMC - PubMed

[9] Ramana K. V.; Kandi S.; Bharatkumar V.; Sharada C. V.; Rao R.; Mani R.; Rao S. D. Invasive fungal infections: a comprehensive review. Am. J. Infect. Dis. Microbiol. 2013, 1, 64–69. 10.12691/ajidm-1-4-2. - DOI

[10] Ramana K. V.; Kandi S.; Bharatkumar V.; Sharada C. V.; Rao R.; Mani R.; Rao S. D. Invasive fungal infections: a comprehensive review. Am. J. Infect. Dis. Microbiol. 2013, 1, 64–69. 10.12691/ajidm-1-4-2. - DOI

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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References

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