Efﬁcient Electrocatalytic Approach to Spiro[Furo[3,2- b ]pyran-2,5 (cid:48) -pyrimidine] Scaffold as Inhibitor of Aldose Reductase

: A continuously growing interest in convenient and ‘green’ reaction techniques encourages organic chemists to elaborate on new synthetic methodologies. Nowadays, organic electrochemistry is a new useful method with important synthetic and ecological advantages. The employment of an electrocatalytic methodology in cascade reactions is very promising because it provides the combina-tion of the synthetic virtues of the cascade strategy with the ecological beneﬁts and convenience of electrocatalytic procedures. In this research, a new type of the electrocatalytic cascade transformation was found: the electrochemical cyclization of 1,3-dimethyl-5-[[3-hydroxy-6-(hydroxymethyl)-4-oxo-4 H -pyran-2-yl](aryl)methyl]pyrimidine-2,4,6(1 H ,3 H ,5 H )-triones was carried out in alcohols in an undivided cell in the presence of sodium halides with the selective formation of spiro[furo[3,2-b ]pyran-2,5 (cid:48) -pyrimidines] in 59-95% yields. This new electrocatalytic process is a selective, facile, and efﬁcient way to create spiro[furo[3,2- b ]pyran-2,5 (cid:48) -pyrimidines], which are pharmacologically active heterocyclic systems with different biomedical applications. Spiro[furo[3,2- b ]pyran-2,5 (cid:48) -pyrimidines] were found to occupy the binding pocket of aldose reductase and inhibit it. The values of the binding energy and Lead Finder’s Virtual Screening scoring function showed that the formation of protein–ligand complexes was favorable. The synthesized compounds are promising for the inhibition of aldose reductase. This makes them interesting for study in the treatment of diabetes or similar diseases.


Introduction
Privileged structures or scaffolds have become an important way to produce pharmaceutically active compounds [1]. Merck researchers were the first, who used this definition in the study on benzodiazepines [2]. These privileged scaffolds generally have a rigid heterocyclic system with a special orientation of the functional substituents for target recognition.
Cascade reactions or domino reactions are often used as efficient strategies in the synthesis of complex organic molecules since they ensure multiple transformations via a series of one-pot reactions. The design and development of cascade reactions is a rapidly expanding area of research in the field of organic synthesis [3].
The elaboration of convenient and efficient methods of synthesis of privileged scaffolds in one-pot cascade reactions is one of the important aims of organic chemistry.
Organic electrochemical synthesis has become a useful method with important synthetic and ecological advantages in the last few decades [4][5][6]. However, the usage of the electrochemical methods is generally limited by equipment complexity and long reaction times.
X-ray diffraction data were collected at 100K on a Bruker Quest D8 diffractometer (Billerica, MA, USA) equipped with a Photon-III area detector (graphite monochromator, shutterless ϕand ω-scan technique) using Mo Kα radiation. The intensity data were integrated using the SAINT program [41] and were corrected for absorption and decay using SADABS [42]. The structure was solved via direct methods using SHELXT [43] and refined on F2 using SHELXL-2018 [44]. All non-hydrogen atoms were refined with individual anisotropic displacement parameters. The location of atom H5 was found from the electron density difference map; it was refined with an individual isotropic displacement parameter. All other hydrogen atoms were placed in ideal calculated positions and refined as riding atoms with relative isotropic displacement parameters. The SHELXTL program suite1 was used for molecular graphics.

Results and Discussion
In this paper, we report the data on the selective and efficient cascade electrocatalytic
Thus, at the beginning of our study, MeOH was used as a solvent and alkali metal bromides were used as mediators. Under these electrolysis conditions in an undivided cell after 2 F/mol of electricity were passed, spiro[furo [3,2-b]pyran-2,5′-pyrimidine] 2a was obtained in 59-65% yields (Entries 1-3, Table 1). Under these electrolysis conditions  (5 mmol    The structure of the compound 2a was additionally confirmed via NMR spectroscopy using 2D 1 H-13 C HSQC and 1 H-13 C HMBC experiments. The assignment of 1 H and 13 C signals in the NMR spectra was carried out and the chemical shifts correlated well with the structure of 2a. It should be noted that the carbon atoms of the amide group, as well as the signals of protons and carbons of methyl residues, had chemically nonequivalent natures; therefore, they had different chemical shifts. Key interactions are indicated In the first step, to estimate the synthetic potential of the electrocatalytic method and improve the electrochemical conditions, the electrocatalytic cyclization of 1,3-dimethyl-5-[[3-hydroxy-6-(hydroxymethyl)-4-oxo-4H-pyran-2-yl](phenyl)-methyl]pyrimidine-2,4,6 (1H,3H,5H)-trione 1a in alcohols as a solvent in an undivided cell in the presence of alkali metal halides was specially studied (Scheme 1, Table 1).
Other alcohols, namely ethanol, and n-propanol, were less efficient as solvents compared with methanol such that the yields of 2a were 64% and 60% (Entries 8 and 9, Table 1 Table 2).
In all these electrocatalytic processes, after the electrolysis had ended, the reaction mixture was concentrated to a volume of 4 mL and cooled to 0 • C to crystallize the solid product, which was then filtered out, twice rinsed with an ice-cold ethanol/water solution (1:1 v/v, 4 mL), and dried under reduced pressure.
The structure of all new compounds 2a-i was confirmed using 1 H, 13 C NMR, and IR spectroscopy, as well as mass spectrometry data. For all compounds, only one set of signals was observed in the 1 H and 13 C NMR spectra.
The structure of the compound 2a was additionally confirmed via NMR spectroscopy using 2D 1 H-13 C HSQC and 1 H-13 C HMBC experiments. The assignment of 1 H and 13 C signals in the NMR spectra was carried out and the chemical shifts correlated well with the structure of 2a. It should be noted that the carbon atoms of the amide group, as well as the signals of protons and carbons of methyl residues, had chemically nonequivalent natures; therefore, they had different chemical shifts. Key interactions are indicated by arrows in Figure 1. Complete correlation of signals: The structure of compound 2f was confirmed using an X-ray diffraction study (Supplementary Material (Figures S19 and S20) and Figure 2).  The structure of compound 2f was confirmed using an X-ray diffraction study (Supplementary Material (Figures S19 and S20) and Figure 2). The structure of compound 2f was confirmed using an X-ray diffraction study (Supplementary Material (Figures S19 and S20) and Figure 2). Given all the above results and taking into consideration the data on electrocatalytic reactions mediated by iodides [46][47][48], the following mechanism for the electrocatalytic cyclization  Given all the above results and taking into consideration the data on electrocatalytic reactions mediated by iodides [46][47][48], the following mechanism for the electro- The evolution of hydrogen was the cathodic process, which was accompanied by methoxide anion generation. The formation of iodine was an anodic process and the corresponding iodine color was observed at the anode when the electrolysis was conducted without stirring of the reaction mixture.
The evolution of hydrogen was the cathodic process, which was accompanied by methoxide anion generation. The formation of iodine was an anodic process and the corresponding iodine color was observed at the anode when the electrolysis was conducted without stirring of the reaction mixture.
Aldose reductase catalyzes the reduction of aldehydes and acids. It participates in glucose into sorbitol transformation [49], which is the first step in fructose formation. Inhibitors of aldose reductase are employed for the treatment of diabetic peripheral neuropathy [50]. Computational chemistry, docking in particular, is a tool that is applied in drug development [51]. It allows for getting insights into protein-ligand interactions and reduces the time and effort directed toward the development of potential drugs [51,52].
The cavity of aldose reductase is divided by Trp111 into the catalytic subpocket and the specificity pocket. The catalytic pocket is related to the catalytic mechanism and is represented by Tyr48, Lys77, and His110 residues [59][60][61]. However, almost all inhibitory activity is related to Trp20 and, in several cases, Leu300 enhances the intercalation of inhibitor between these two residues [51].

Trp20
Tyr209 Ser210 Formed an interaction with the key residue Trp20. Formed additional interactions with Tyr209 and Ser210 (which are binding residues in the reference ligand) [51].
Electrochem 2021, 2, FOR PEER REVIEW 11 Formed an interaction with the key residue Trp20. Formed additional interactions with Tyr209 and Ser210 (which are binding residues in the reference ligand) [51].
Formed an interaction with the key residue Trp20. Formed additional interactions with Asn160 and Cys298. Formed an interaction with the key residue Trp20. Formed additional interactions with Ser210 (which is a binding residue in the reference ligand), Trp111, Asn160, Tyr209, and Cys298. Formed an interaction with the key residue Trp20. Formed an additional interaction to Ser110 (which is a binding residue in the reference ligand).

Tyr20
Asn160 Tyr209 Formed an interaction with the key residue Trp20. Formed additional interactions with Asn160 and Cys298.  Formed an interaction with the key residue Trp20. Formed additional interactions with Tyr209 and Ser210 (which are binding residues in the reference ligand) [51].
Formed an interaction with the key residue Trp20. Formed additional interactions with Asn160 and Cys298. Formed an interaction with the key residue Trp20. Formed additional interactions with Ser210 (which is a binding residue in the reference ligand), Trp111, Asn160, Tyr209, and Cys298. Formed an interaction with the key residue Trp20. Formed an additional interaction to Ser110 (which is a binding residue in the reference ligand). The selection of the best pose was per-Trp20 Trp111 Asn160 Tyr209 Ser210 Cys298 Formed an interaction with the key residue Trp20. Formed additional interactions with Ser210 (which is a binding residue in the reference ligand), Trp111, Asn160, Tyr209, and Cys298.  Formed an interaction with the key residue Trp20. Formed additional interactions with Tyr209 and Ser210 (which are binding residues in the reference ligand) [51].
Formed an interaction with the key residue Trp20. Formed additional interactions with Asn160 and Cys298. Formed an interaction with the key residue Trp20. Formed an additional interaction to Ser110 (which is a binding residue in the reference ligand). The selection of the best pose was per-

Ser210
The only interaction revealed was with Ser210. Formed an interaction with the key residue Trp20. Formed an additional interaction to Ser110 (which is a binding residue in the reference ligand). The selection of the best pose was performed manually.

Tyr20
Asn160 Tyr209 Ser210 Formed an interaction with the key residue Trp20. Formed an additional interaction to Ser110 (which is a binding residue in the reference ligand). The selection of the best pose was performed manually. Formed an interaction with the key residue Trp20. Formed additional interactions with Ser210 and Ser214 (which are binding residues in the reference ligand).

Trp20 Leu300
Formed an interaction with the key residue Trp20. Formed an additional binding with Leu300. Formed an interaction with the key residue Trp20. Formed additional interactions with Ser210 and Ser214 (which are binding residues in the reference ligand).

Trp20
Tyr48 Trp111 Asn160 Tyr209 Formed an interaction with the key residue Trp20. Formed an additional interaction with Tyr48 (which is a binding residue in the reference ligand), Trp111, Asn160, and Tyr209. Formed an interaction with the key residue Trp20. Formed an additional interaction with Tyr48 (which is a binding residue in the reference ligand), Trp111, Asn160, and Tyr209.
Formed an interaction with the key residue Trp20. Formed additional interactions with Ser210 and Ser214 (which are binding residues in the reference ligand).

Trp20
Val47 Tyr48 Formed an interaction with the key residue Trp20. Formed an additional interaction with Val47 and Tyr48 (which are binding residues in the reference ligand) [51].

Trp20
Ser210 Ser214 Formed an interaction with the key residue Trp20. Formed additional interactions with Ser210 and Ser214 (which are binding residues in the reference ligand).  Trp20  Tyr48  Trp111  Asn160  Tyr209 Formed an interaction with the key residue Trp20. Formed an additional interaction with Tyr48 (which is a binding residue in the reference ligand), Trp111, Asn160, and Tyr209. The reference co-crystallized ligand [51].

Trp20
Val47 Tyr48 Formed an interaction with the key residue Trp20. Formed an additional interaction with Val47 and Tyr48 (which are binding residues in the reference ligand) [51]. Formed an interaction with the key residue Trp20. Formed an additional interaction with Tyr48 (which is a binding residue in the reference ligand), Trp111, Asn160, and Tyr209. The reference co-crystallized ligand [51].
Despite a good position and several hydrogen bonds forming with key amino acids (Cys298, Ser214, Ser210, Trp20), the nitro derivative 2h showed the lowest binding energy among the examined compounds, which was −6.399 kcal/mol. The LFVS value was also moderate, which was −7.686. Nevertheless, because of the moderate value and the presence of a key interaction (Trp20), it may be interesting for further investigations in drug development.
Thus, according to docking studies, substituted spiro[furo [3,2-b]pyran-2,5 -pyrimidines] have conformations that may inhibit aldose reductase function. The values of the binding energy and Lead Finder's Virtual Screening scoring function found for this formation of protein-ligand complexes were favorable and, in several cases, it may surpass the co-crystallized inhibitor. Thus, substituted spiro[furo [3,2-b]pyran-2,5 -pyrimidines] are promising for the further investigation of their inhibitory activity related to aldose reductase as its inhibitors are applied in the treatment of diabetes or similar diseases.
This new electrocatalytic cyclization is a facile path to the earlier unknown substituted spiro[furo [3,2-b]pyran-2,5 -pyrimidines] containing both barbituric and kojic acid fragments, which are promising compounds for different biomedical applications, with anticonvulsants, anti-AIDS agents, and anti-inflammatory remedies among them.
This efficient electrocatalytic procedure utilizes simple equipment, an undivided cell, and an available and cheap mediator, namely, sodium iodide. It is easily carried out and the isolation procedure is very simple. Thus, this new method is valuable from the viewpoint of environmentally benign, diversity-oriented, large-scale processes. All these advantages make this method valuable for the synthesis of new potential drug libraries.
It was found that substituted spiro[furo[3,2-b]pyran-2,5 -pyrimidines] may occupy the binding pocket of aldose reductase to inhibit its action. The values of the binding energies and Lead Finder's Virtual Screening scoring functions showed that the formation of protein-ligand complexes was favorable. The synthesized compounds are promising for further investigation of their inhibitory activity related to aldose reductase, it makes them interesting for the treatment of diabetes or similar diseases.