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. 2020 Dec 11:8:559262.
doi: 10.3389/fchem.2020.559262. eCollection 2020.

Mono-Alkylated Ligands Based on Pyrazole and Triazole Derivatives Tested Against Fusarium oxysporum f. sp. albedinis: Synthesis, Characterization, DFT, and Phytase Binding Site Identification Using Blind Docking/Virtual Screening for Potent Fophy Inhibitors

Yassine Kaddouri  1 , Farid Abrigach  1 , Sabir Ouahhoud  2 , Redouane Benabbes  2 , Mohamed El Kodadi  1   3 , Ali Alsalme  4 , Nabil Al-Zaqri  4   5 , Ismail Warad  6 , Rachid Touzani  1
Affiliations

Mono-Alkylated Ligands Based on Pyrazole and Triazole Derivatives Tested Against Fusarium oxysporum f. sp. albedinis: Synthesis, Characterization, DFT, and Phytase Binding Site Identification Using Blind Docking/Virtual Screening for Potent Fophy Inhibitors

Yassine Kaddouri et al. Front Chem. .

Abstract

Twelve recent compounds, incorporating several heterocyclic moieties such as pyrazole, thiazole, triazole, and benzotriazole, made in excellent yield up to 37-99.6%. They were tested against Fusarium oxysporum f. sp. albedinis fungi (Bayoud disease), where the best results are for compounds 2, 4, and 5 with IC50 = 18.8-54.4 μg/mL. Density functional theory (DFT) study presented their molecular reactivity, while the docking simulations to describe the synergies between the trained compounds of dataset containing all the tested compounds (57 molecules) and F. oxysporum phytase domain (Fophy) enzyme as biological target. By comparing the results of the docking studies for the Fophy protein, it is found that compound 5 has the best affinity followed by compounds 2 and 4, so there is good agreement with the experimental results where their IC50 values are in the following order: 74.28 (5) < 150 (2) < 214.10 (4), using Blind docking/virtual screening of the homology modeled protein and two different tools as Autodock Vina and Dockthor web tool that gave us predicted sites for further antifungal drug design.

Keywords: DFT; Fusarium oxysporum; antifungal; docking; pyrazole; triazole.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The reaction procedure for the preparation of compounds 1–12 (pathway A,B).
Figure 2
Figure 2
The chemical structure of N-((1H-pyrazol-1-yl)methyl)thiazol-2-amine, 7.
Figure 3
Figure 3
1H NMR spectrum of N-((1H-pyrazol-1-yl)methyl)thiazol-2-amine, 7.
Figure 4
Figure 4
13C NMR spectrum of N-((1H-pyrazol-1-yl)methyl)thiazol-2-amine, 7.
Figure 5
Figure 5
Two-dimensional NMR COSY spectrum of N-((1H-pyrazol-1-yl)methyl)thiazol-2-amine, 7.
Figure 6
Figure 6
Synthesis route and chemical structures of the mono-alkylated pyrazole and triazole ligands.
Figure 7
Figure 7
The F.o.a. Petri plates picture for compounds 2, 4, and 5.
Figure 8
Figure 8
Lipophilicity and antifungal activity plot.
Figure 9
Figure 9
MEP surfaces for the three best anti-Fusarium candidates 2 (A), 4 (B), and 5 (C), where the negative regions (black circle) are related to electrophilic reactivity, whereas the positive regions (red circle) are for nucleophilic reactivity.
Figure 10
Figure 10
Structure alignment of homology modeled Fophy protein (colored) and its template 3K4P (blue).
Figure 11
Figure 11
Three-dimensional presentation of the three binding sites found by Blind docking/virtual screening.
Figure 12
Figure 12
The two-dimensional interactions of ligand 2, 4, and 5 with the chosen active site in the Fophy protein.
Figure 13
Figure 13
Structure alignment of Blind docking/virtual screening results on Aspergillus niger phytase protein and Fophy.
Figure 14
Figure 14
Blind docking/virtual screening of Fophy protein using Autodock Vina (A) and Dockthor (B).
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References

    1. Abrigach F., Karzazi Y., Benabbed R., Elyoubi M., Khoutoul M., Taibi N., et al. (2017). Synthesis, biological screening, POM and 3D-QSAR analyses of some novel pyrazolic compounds. Med. Chem. Res. 26, 1784–1795. 10.1007/s00044-017-1888-8 - DOI
    1. Abrigach F., Khoutoul M., Merghache S., Oussaid A., Lamsayah M., Zarrouk A., et al. (2014). Antioxidant activities of N-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)pyridin-4-amine derivatives. Der. Pharma. Chem. 6, 280–285.
    1. Abrigach F., Rokni Y., Takfaoui A., Khoutoul M., Doucet H. (2018). In vitro screening, homology modeling and molecular docking studies of some pyrazole and imidazole derivatives biomedicine & pharmacotherapy in vitro screening, homology modeling and molecular docking studies of some pyrazole and imidazole derivatives. Biomed. Pharmacother. 103, 653–661. 10.1016/j.biopha.2018.04.061 - DOI - PubMed
    1. Akhtar J., Khan A. A., Ali Z., Haider R., Shahar Yar M. (2017). Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem. 125, 143–189. 10.1016/j.ejmech.2016.09.023 - DOI - PubMed
    1. Alegaon S. G. K. R. A., Garg M. K., Dushyant K., Vinod D. (2014). 1,3,4-Trisubstituted pyrazole analogues as promising anti-inflammatory agents. Bioorg. Chem. 54, 51–59. 10.1016/j.bioorg.2014.04.001 - DOI - PubMed

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