Novel β-keto–enol Pyrazolic Compounds as Potent Antifungal Agents. Design, Synthesis, Crystal Structure, DFT, Homology Modeling, and Docking Studies

Abstract

A new family of promising inhibitors bearing -keto-enol functionality with greatly improved pharmacophore properties has prepared. Herein, a series of novel derivatives of -keto-enol group embedded with pyrazolic moiety has been designed and synthesized via a one-step procedure using mixed Claisen condensation in the attempt to develop potential antifungal agents. The structures of the synthesized compounds were confirmed by elemental analysis, FT-IR, ESI/LC-MS, 1 H and 13 C NMR. In addition, X-ray diffraction analysis (XRD) was used to determine the single crystal structure of compound 10. All the newly compounds have been evaluated for their in vitro antifungal and antibacterial activities. Interestingly, the results indicate that most of the compounds display notable antifungal activity close to that of the benomyl fungicide taken as the standard drug. For the most active compound and for benomyl, a correlation has been evidenced between the experimental antifungal activity and the theoretical predictions by DFT calculations and molecular docking against Fgb1 protein.

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

“…It is worth noting that the present results are the best among previously tested analogues against the FOA fungus. 21 , 33 In connection with a pronounced biological interest in heterocyclic compounds, this study suggests that the nature of the R substituent ( Figure 2 ) should be considered seriously to be able to tune properties and determine the structural activity ratio for this new class of antifungal agent.…”

“…These products are presumably in anticonformation isomeric forms as already demonstrated for similar products analyzed too by single-crystal X-ray diffraction. 21 , 33 − 41 …”

“…This trend is confirmed by single-crystal X-ray diffraction, which systematically showed the β-keto-enol in this substance class, along with a mesomeric effect. 21 , 33 − 41 We recall that there are two driving forces responsible for the formation of keto-enol isomers in solution: 42 (i) the electronic force, in which the formation of the enol isomer is controlled by the electronegativity of the R and R′ substituents fixed on the β-diketone (R′COCH 2 COR) and (ii) the resonance force (mesomeric effect), which has priority over the inductive effect when one or two substituents R and R′ are aromatic.…”

Synthesis, Antimicrobial Screening, Homology Modeling, and Molecular Docking Studies of a New Series of Schiff Base Derivatives as Prospective Fungal Inhibitor Candidates

“…However, because of the unavailability of experimental crystal structures of these proteins, homology modeling studies were carried out to construct three-dimensional (3D) structures of Fgb1 and Fophy prior to use in our docking studies. For Fgb1 protein, the model was generated and validated as described previously in our last works [21,22] using the crystal structure of the Rattus norvegicus Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (3SN6_chain B) as a suitable template. Following the same procedure described for the Fgb1 model, the 3D structure of the Fophy protein was also built.…”

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

“…A molecular docking approach was used for the best antifungal derivatives against Fophy. The structure of this approach was constructed using the homology model that has been previously reported in the literature (Soundararajan et al, 2011;Abrigach et al, 2014;Tighadouini et al, 2019;Toubi et al, 2019), to achieve better insight into the ligand-receptor binding interactions and direct future synthesis. In case that there is no cofactor, blind docking, and virtual screening are used in this study for site prediction and protocol validation using Autodock Vina (Seeliger and de Groot, 2010) and Dockthor (Santos et al, 2020).…”