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. 2023 Jul 7;8(28):24901–24911. doi: 10.1021/acsomega.3c01291

Meldrum-Based-1H-1,2,3-Triazoles as Antidiabetic Agents: Synthesis, In Vitro α-Glucosidase Inhibition Activity, Molecular Docking Studies, and In Silico Approach

Satya Kumar Avula †, Saeed Ullah †, Sobia Ahsan Halim †, Ajmal Khan †,*, Muhammad U Anwar †, René Csuk ‡, Ahmed Al-Harrasi †,*, Ali Rostami †,*
PMCID: PMC10357758  PMID: 37483205

Abstract

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A series of novel alkyl derivatives (2–5a,b) and 1H-1,2,3-triazole analogues (7a–k) of Meldrum’s acid were synthesized in a highly effective way by using “click” chemistry and screened for in vitro α-glucosidase inhibitory activity to examine their antidiabetic potential. 1H NMR, 13C-NMR, and high-resolution electrospray ionization mass spectra (HR-ESI-MS) were used to analyze each of the newly synthesized compounds. Interestingly, these compounds demonstrated high to moderate α-glucosidase inhibitory potency having an IC50 range of 4.63–80.21 μM. Among these derivatives, compound 7i showed extraordinary inhibitory activity and was discovered to be several times more potent than the parent compound Meldrum (1) and the standard drug acarbose. Later, molecular docking was performed to understand the binding mode and the binding strength of all the compounds with the target enzyme, which revealed that all compounds are well fitted in the active site of α-glucosidase. To further ascertain the structure of compounds, suitable X-ray single crystals of compounds 5a, 7a, and 7h were developed and studied. The current investigation has shown that combining 1H-1,2,3-triazole with the Meldrum moiety is beneficial. Furthermore, this is the first time that the aforementioned activity of these compounds has been reported.

1. Introduction

Diabetes mellitus (DM) is a chronic metabolic disease and one of the leading causes of death worldwide due to its severe complications. Long-term high blood glucose levels in diabetic individuals cause several problems, including microvascular issues or the loss of extremely small blood vessels in the body, which can lead to catastrophic kidney, eye, nerve, and heart ailments.1,2 Type 2 DM (T2DM) affects the majority of patients, and the disease prevalence is becoming a growing public health concern. The World Health Organization (WHO) predicted in 2006 that the number of patients with T2DM will rise to 366 million by 2030, accounting for 9.9% of the world’s adult population. Several lifestyle variables are involved in increasing the risk of T2DM, including obesity and weight, physical inactivity, cigarette smoking, low-fiber diet with a high glycemic index, and depression.3,4 Currently, the most effective antidiabetic therapeutic strategy is reducing blood glucose levels. Because α-glucosidase is a critical enzyme in the conversion of complex carbohydrates (polysaccharides) to simple sugars (monosaccharides), α-glucosidase inhibitors (α-GIs) have taken a unique place in drug development. α-Glucosidase is located in the brush border of the small intestine and selectively hydrolyzes terminal 1-4-α-glucosidase residues (starch or disaccharides) to produce glucose. By delaying the digestion of carbohydrates, α-GI limits the rate of glucose absorption and avoids the progression of the impaired glucose tolerance factor (GTF) to T2DM. It has been discovered that limiting the effect of dietary carbohydrates on blood sugar is critical.5,6

Meldrum’s acid, that is, 2,2-dimethyl-1,3-dioxan-4,6-dione (R1 = Me, R2, R3 = H), was prepared in 1908 by Andrew Norman Meldrum; however, the exact structure was revealed in 1948 by Davidson and Benhard (Scheme 1).7 Meldrum’s acid derivatives are bench-stable, easily accessible compounds that act as crucial organic building blocks, which are fundamental components in organic synthesis and flourishing applications in the synthesis of natural products and multicomponent reactions (MCRs).8−14 Meldrum’s acid derivatives have been used as substrates for a wide range of reactions with applications in the total synthesis of natural products and the synthesis of biologically significant compounds (e.g., taiwanaquinol B),15 at-turmerone and α-curcumene,16 and coumarin derivatives.17 Furthermore, this medicine is reasonably priced. Meldrum’s acid (1) is regarded as a “standard” antibiotic due to its excellent antibacterial effectiveness, biological activity, and few side effects (Figure 1).18

Scheme 1. Synthesis of Meldrum’s Acid (1).

Scheme 1

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Figure 1.

Figure 1

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Chemical structure of Meldrum’s acid (1).

Apart from the extensive utility in organic synthesis, Meldrum’s acid derivatives show biological potential as antioxidant and antimalarial agents, including α-glucosidase and cholinesterase inhibitory activities.19,20

On the other hand, the use of 1H-1,2,3-triazole compounds in pharmaceuticals and agrochemicals has grown.21 Due to its numerous and varied uses in the fields of biomedical, biochemical, and materials sciences,22 these 1H-1,2,3-triazole compounds play a crucial role in organic chemistry. Over the last few decades, the number of compounds with a triazole moiety has significantly increased. In addition, heterocycles with 1H-1,2,3-triazole scaffolds are known to possess biological properties such as antimicrobial,23 antibacterial,24 antiviral,25 anti-HIV,26 anti-inflammatory,27 and anticancer properties.28 Our research group has reported several synthesized bioactive 1H-1,2,3-triazole analogues with potential biological activities including α-glucosidase inhibitors (Figure 2).29−31

Figure 2.

Figure 2

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Rational design of the current study.

In this context, our recommendation was to alter Meldrum’s acid by adding an alkyl or N-heterocyclic moieties. To know the dual potential of these molecules, we synthesized novel derivatives of meldrum (1) linked with 1H-1,2,3-triazole, which were further tested against the α-glucosidase enzyme, and their mode of binding with the enzyme was determined through molecular docking. To the best of our knowledge, this is the first study on hybrid 1H-1,2,3-triazole derivatives with Meldrum molecules.

2. Results and Discussion

2.1. Chemistry

2.1.1. Synthesis of Alkyl Derivatives of Meldrum’s Acid (2–5a,b)

The synthetic scheme of alkyl derivatives of Meldrum’s acid is depicted in Scheme 2. In pursuing our aim to synthesize alkyl derivatives, we have designed and synthesized novel analogues of Meldrum. The desired alkyl derivatives of Meldrum (2–5a,b) were achieved by a three-step protocol with condensation and reduction, followed by an alkylation reaction. Thereby, in the initial step, Meldrum 1 reacted with p-anisaldehyde in pyridine at room temperature for 15 h to afford a high yield (97%) of compound 2. The following step is compound 2 undergoing reduction with NaBH4 in EtOH at 0 °C to rt for 2–3 h to furnish compound 3 in high yield (98%). The final step produced high yields (96–98%) of alkyl derivatives of Meldrum’s acid (5a,b) from compound 3 when it was treated with alkyl bromide (4a,b) in a DMF solvent with potassium carbonate as a base for 18 h at room temperature (Table 1).13,32,33

Scheme 2. Reagents and Conditions: (a) Pyridine, Room Temperature, 15 h, 97%; (b) NaBH4, EtOH, 0 °C to Room Temperature, 2–3 h, 98%; and (c) R1-Br (Different Alkyl Bromides, 4a,b), K2CO3, DMF, Room Temperature, 18 h, 96–98% (5a,b).

Scheme 2

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Table 1. Synthesis of Alkyl Derivatives of Meldrum’s Acid (5a,b).
reactant reagent (4a,b) R1-group alkyl derivatives of meldrum (5a,b) yield of (5a,b) (%)a
3 4a propargyl 5a 96
3 4b benzyl 5b 98
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a

Yields refer to pure isolated products.

The distinctive signals for acetylenic (−CH≡C) and propargyl methylene (−CH2) protons can be seen in the 1H NMR spectra of compound 5a at δ 2.09 and 2.92, respectively. Acetylene (−CH≡C−) and propargyl methylene (−CH2) groups are represented by signals in the 13C NMR spectra of compound 5a at δ 78.3, 72.9, and 30.2. The protonated molecular ion at (m/z) 303.2076 [M + H+] was detected by HRMS (ESI), providing additional evidence of compound 5a.

Figure 3 shows the structure of compound 5a, which X-ray crystallography unambiguously confirmed. Its crystals were grown from EtOAc and dichloromethane (DCM) (1:1) solution.

Figure 3.

Figure 3

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X-ray crystal structure of 5a.

2.3. Synthesis of 1H-1,2,3-Triazole Derivatives of Meldrum’s Acid (7a–k)

Scheme 3 illustrates the process for synthesizing Meldrum’s acid 1H-1,2,3-triazole derivatives. Chemistry used in the “click” reaction produced the necessary 1H-1,2,3-triazole derivatives of Meldrum’s acid (7a–k). The intended products, 1H-1,2,3-triazole derivatives of Meldrum’s acid (7a–k), were produced in step 1 with high yields (96–98%) (Table 2) by reacting 5a with various substituted aromatic azides (6a–k) in the presence of Hünig’s base and copper iodide (CuI) in acetonitrile (MeCN).34−37

Scheme 3. Reagents and Conditions: (a) R2–N3 (different substituted aromatic azides, 6a–k), CuI, Et3N, CH3CN, Room Temperature, 3 h, and 7a–k (96–98%).

Scheme 3

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Table 2. Synthesis of 1H-1,2,3-Triazole Derivatives of Meldrum’s Acid (7a–k).

reactant R2-Group 1H-1,2,3-triazole derivatives of meldrum’s acid (7a–k) yield of (7a–k) (%)a
5a Ph 7a 96
5a 2-MeC6H4 7b 98
5a 2-MeOC6H4 7c 98
5a 2-F3CC6H4 7d 96
5a 4-MeOC6H4 7e 98
5a 3-F3CC6H4 7f 96
5a 3-BrC6H4 7g 97
5a 4-BrC6H4 7h 97
5a 4-ClC6H4 7i 96
5a 4-FC6H4 7j 97
5a 4-F3CC6H4 7k 96
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a

Yields refer to pure isolated products.

By the appearance of a distinctive singlet at δ 7.50–7.93 in their respective 1H NMR spectra, which can be attributed to the H-5′ proton of the triazole ring, the production of 1H-1,2,3-triazole derivatives of Meldrum’s acid (7a–k) was confirmed. Furthermore, the synthesized 1H-1,2,3-triazole hybrids of Meldrum’s acid (7a–k) displayed the characteristic triazole ring carbon signals between δ 120–125 and 142–145 as well as the phenyl ring carbon signals at δ 100–165 in their 13C NMR spectra. HRMS provided additional support for the 1H-1,2,3-triazole Meldrum derivatives (7a–k) in terms of their structural details.

Figure 4 shows the structures of compounds 7a and 7h, which X-ray crystallography clearly validated. These two compound crystals were grown from the gradual solvent evaporation of EtOAc.

Figure 4.

Figure 4

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X-ray crystal structures of compounds 7a and 7h.

By using spectrum data analysis (1H & 13C NMR, HRMS, and 19F NMR spectroscopy when appropriate), the structures of all the synthesized compounds (2–5a,b and 7a–k) were confirmed.

3. Biological Activity

The general structural feature of the synthesized Meldrum’s acid derivatives (5a,b and 7a–k) are presented in Figure 5. The three changeable moieties (meldrum, alkyl, and triazole) were thought to form a stiff motif with an aromatic group connected to Meldrum’s acid moiety, which primarily governs the different degrees of activity. The inhibitory action of α-glucosidase is influenced by a wide variety of functional groups, including both electronegative and electropositive ones.

Figure 5.

Figure 5

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General structural feature of the synthesized Meldrum’s acid derivatives.

3.1. In Vitro α-Glucosidase Inhibition

To investigate the pharmacological importance of these synthesized molecules, all the hybrids were evaluated for their antidiabetic capability by inhibiting α-glucosidase. The parent compound (1) along with compounds 2–3 and 5a was not able to inhibit α-glucosidase (above 50%) and thus considered inactive; however, compound 5b exhibited notable inhibition with the addition of R1-benzyl (IC50 = 80.21 ± 0.75 μM), as compared to acarbose (IC50 = 873.34 ± 1.67 μM) (Figure 6).

Figure 6.

Figure 6

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In vitro α-glucosidase inhibition of Meldrum acid’s derivatives (1–5b).

Figure 7 shows compounds 7a–k with similar R-groups like Scheme 1 compounds, while R1-propargyl is converted into triazole, which is constant and R2 is varied among all members, which determine the importance of different groups in the inhibition of α-glucosidase. For instance, 7a, with the addition of R2-phenyl, exhibited several times potent anti-α-glucosidase activity (IC50 = 46.43 ± 0.72 μM), as compared to acarbose (a marketed drug with IC50 = 873.34 ± 1.67 μM). In compound 7b, the substitution of R2-2-MeC6H4 further enhanced the antidiabetic capability with an IC50 value of 20.61 ± 0.35 μM, as compared to 7a. On the other hand, the addition of 2-MeOC6H4 in 7c slightly reduced the α-glucosidase inhibition (IC50 = 27.82 ± 0.31 μM), as compared to 7b. Like 7b and 7c, a slight decline in the α-glucosidase inhibition was observed for 7d–7f upon addition of 2-F3CC6H4, 4-MeOC6H4, and 3-F3CC6H4 with IC50 values of 37.04 ± 0.51, 39.86 ± 0.68, and 41.42 ± 0.53 μM, respectively. However, the substitution of 3-BrC6H4 and 4-BrC6H4 in 7g and 7h, respectively, resulted in improved antidiabetic potential with IC50 values of 32.19 ± 0.27 and 29.62 ± 0.17 μM, respectively, as compared to 7b and 7c. In contrast, the addition of 4-ClC6H4 in 7i interestingly increased the α-glucosidase inhibitory potency of 7i (IC50 = 4.63 ± 0.11 μM) and turned it to be the most potent antidiabetic agent among other members of this series, whereas the addition of 4-FC6H4 in 7j decreased the antidiabetic property of 7j (IC50 = 23.98 ± 0.65 μM), as compared to 7i. Moreover, the incorporation of 4-F3CC6H4 in 7k further declined its biological activity (IC50 = 28.52 ± 0.34 μM), even though 7k exhibited a several-fold more potent anti-α-glucosidase effect as compared to acarbose. Overall, the structure–activity relationship revealed that the triazole basic skeleton is the key component for the anti-α-glucosidase activity, while different R2 attached groups are also responsible for their varied inhibitory activities. The structure–activity relationship (SAR) of these compounds is depicted in Figure 7.

Figure 7.

Figure 7

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In vitro α-glucosidase inhibition and SAR of Meldrum’s acid derivatives (7a–k).

3.2. Molecular Docking Studies

We have performed docking studies of active analogues including 5b and 7a–k to determine their binding strength with the active site residues of α-glucosidase. Preceding to the docking of our active hits, we redocked the cocrystalized ligand (competitive inhibitor maltose) in the active site of the enzyme–ligand complex to validate the docking procedure. The redocking results showed excellent superimposition of the docked conformation of maltose on its cocrystalized conformation with a root-mean-square deviation (RMSD) value of 0.32 Å and docking score of −6.66 kcal/mol. The known inhibitor binds with the catalytic triad (Asp215, Glu277, and Asp352). In addition, it also forms interactions with Asp69, His112, Arg213, His351, and Arg442. It indicates that the docking method can correctly identify the binding modes of newly synthesized ligands.

Molecular docking clearly demonstrates the pattern of ligand binding in the active site of the enzyme, which reflects the reason of their varied inhibitory potency and correlates with the experimental results. We observed that the Meldrum moiety of the compounds plays an important role in binding with the active site residues, whereas the methoxy-substituted phenyl ring is fitted in the core of the active site, while the triazole-substituted R2 group resides at the entrance loop of the active site. The docked orientations of all the compounds are shown in Figure 8.

Figure 8.

Figure 8

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(A) Docked conformations of compounds (shown in the magenta ball and stick model) are shown in the active site of the α-glucosidase enzyme (presented in the yellow surface model). (B). Binding interactions of ligands with the active site residues are shown. Only those residues which are involved in the H-bonding or hydrophobic interactions with ligands are displayed for clarity purpose. The ligand residue H-bonds are depicted in black dashed lines, and hydrophobic interactions are presented in green dashed lines. The interacting residues are shown in the green ball and stick model and in orange surface presentation, while compounds are shown in the magenta ball and stick model.

The binding mode of the most active compound, 7i, better explains its higher inhibitory potential; the Meldrum moiety of 7i fits beneath the core of the active site between Glu277, Gln279, Phe303, Asp352, Gln353, Glu411, and Arg442. The ligand does not directly interact with the residues of the catalytic triad (Asp215, Glu277, and Asp352), which is acceptable that the Meldrum moiety cannot form hydrogen bonds (H-bonds) with those acidic residues. However, the Meldrum of 7i mediates strong H-bonds with the side chains of the Gln279 and Arg442 at 3.06 and 3.08 Å, respectively. The Meldrum-substituted methoxyphenyl ring of 7i fits well at the hydrophobic groove above the core of the active site, which is composed of Tyr72, Val109, His112, Tyr158, Phe159, Phe178, Gln182, and Val216. The triazole moiety of the compound did not form any hydrophilic interaction with the active site due to its small size and expanded nature of the entrance loop and however fitted well in between several residues (Asp242, His280, Thr306, Asp307, Thr310, Ser311, Pro312, and Arg315) at the entrance of the active site. The binding mode of 7i is shown in Figure 9. The compound 7i exhibited −8.62 kcal/mol docking score (DS), which is higher than the DS of all the compounds; it also validates the experimental findings (Table 3).

Figure 9.

Figure 9

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Binding mode of the most active compound (7i) is shown in the active site of α-glucosidase with its enhanced view. The entrance loop of the active site is shown in the pink surface model, the active site core is presented in the cyan surface model, and the hydrophobic groove above the core is depicted in the yellow surface presentation. The ligand is presented in the magenta ball and stick model, and H-bonds are shown in black dashed lines.

Table 3. Molecular Docking Results of Meldrum’s Acid Derivativesa.

      protein–ligand interaction
compounds IC50 (μM) DS (kcal/mol) ligand atom receptor atom interaction distance
7i 4.63 –8.62 O15 NE2-GLN279 HBA 3.06
O16 NH1-ARG442 HBA 3.08
7b 20.61 –6.90 O16 NE2-GLN279 HBA 2.90
7j 23.98 –6.83 O15 NE2-GLN279 HBA 3.09
7c 27.82 –6.44 O16 NE2-GLN279 HBA 2.92
7k 28.52 –5.83 O53 NH2-ARG213 HBA 3.01
7h 29.62 –4.51 O16 NE2-GLN279 HBA 3.16
6-ring 6-ring-TYR158 π–π 3.86
7g 32.19 –4.32 O15 NE2-GLN279 HBA 3.01
6-ring CB-ARG315 π-H 3.63
7d 37.04 –3.39 O16 NE2-GLN279 HBA 3.10
7e 39.86 –3.30 O16 NE2-GLN279 HBA 3.09
C55 6-ring-PHE178 π-H 3.96
7f 41.42 –3.11 O16 NH1-ARG213 HBA 3.49
O16 NH2-ARG213 HBA 3.38
7a 46.43 –3.09 O16 NH1-ARG442 HBA 2.70
5b 80.21 –2.56 O42 NE2-GLN279 HBA 2.96
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a

DS = docking score, HBA = hydrogen bond acceptor, and HBD = hydrogen bond donor.

The docked conformations of the rest of the compounds were compared with the docked conformation of 7i to understand the SAR of all the compounds. It was observed that the Meldrum ring and the methoxyphenyl ring of the second most active compounds (7b, 7j, and 7c) adopted almost similar orientations like 7i; however, the triazole ring and its substituted R2 moiety of these compounds drastically changed conformation because of the expanded surface of the active site entrance. Due to this conformational change, the Meldrum group of 7b, 7j, and 7c formed only single H-bonds with the side chain of Gln279 and lost one H-bond with Arg442; consequently, their activity was considerably declined as compared to 7i. This is also evident with their docking scores. These compounds exhibited a DS in the range of −6.90 to −6.44 kcal/mol, which is less than the docking score of 7i. The same binding pattern was followed by compounds 7h, 7g, 7d, and 7e. In addition to the H-bond with Gln279, compounds 7h, 7g, and 7e also formed hydrophobic interactions with Tyr158, Arg315, and Phe178, respectively.

When the binding mode of 7k was compared with the docking conformation of 7i, we observed that the triazole and the R2 of 7k took almost similar binding modes like 7i; however, its Meldrum moiety was tilted around 45° from the meldrum of 7i; as a result, the interaction of its Meldrum with Gln279 and Arg442 is totally lost. Due to this conformational variation, the methoxyphenyl ring of 7k was tilted toward Glu277 and Arg213, where the side chain of Arg213 provided H-bonds to the methoxy oxygen of 7k. Interestingly, the ligand 7f was found deeply inserted inside the active site; as a result, its Meldrum moiety fits in the hydrophobic groove instead of the core of the active site, and its R2 group was placed at a position where the Meldrum ring of other compounds is fitted. Therefore, the Meldrum of 7f lost interactions with Glu279 or Arg442 and only stabilized through H-bonds with the side chain of Arg213, while its triazole ring or R2 moiety did not form any interaction. This huge conformational difference was responsible for the further decrease of the biological activity of 7f as compared to 7i. The binding mode of 7a was found to be considerably like the docking conformation of 7f that further validates their similar range of inhibitory affinity. However, its Meldrum moiety was tilted toward Arg442 and mediates a H-bond with the side chain of Arg442. Similarly, the docking conformation of 5b, the least active compound, was compared with that of 7i, which revealed that the Meldrum moiety of 5b mediated only a single H-bond with the side chain of Gln279 but lost bonding with Arg442 or other surrounding residues.

With the docking studies, it was identified that the triazole and its substituted R2 group do not mediate interaction with active site residues but produce conformational changes in compounds, which affect the binding of the Meldrum moiety of compounds with the residues, more specifically Glu279 and Arg442 that play crucial roles in ligand stability. The docking scores and atom-based protein–ligand interactions of all the docked compounds are given in Table 3. The docking results indicate that the known inhibitor (maltose) binds with the catalytic triad (Asp215, Glu277, and Asp352) and mediates H-bonds with Asp69, His112, Arg213, His351, and Arg442, while our ligands interact primarily with Gln279, Arg213, and Arg442.

4. Conclusions

The “click” chemistry was utilized in a highly efficient manner to synthesize a series of novel alkyl derivatives (2–5a,b) and 1H-1,2,3-triazole derivatives (7a–k) of Meldrum’s acid. The structures of the synthesized molecules were characterized, and those were screened for in vitro α-glucosidase inhibitory activity. Among all the tested compounds, 7i displayed highly potent inhibitory activity and was found to be several times more potent than acarbose. Furthermore, the binding pattern of the active molecules was examined through molecular docking, which revealed that the Meldrum moiety is the main constituent and essential part for interaction with active site residues; however, the triazole-substituted R2 group variably changes the position and causes conformational changes that influence the binding of the Meldrum moiety; as a result, the inhibitory potency of compounds is changed.

5. Experimental Section

5.1. General

All reagents were obtained from Sigma-Aldrich, Germany. The silica gel for column chromatography was 100–200-mesh. Solvents were purified by following standard procedures. The high-resolution electrospray ionization mass spectra (HR-ESI-MS) were recorded on an Agilent 6530 LC Q-TOF instrument. The 1H and 13C NMR spectra were recorded on a NMR spectrometer (Bruker: 600 MHz for 1H, 150 MHz for 13C and 564 MHz for 19F) using CDCl3 as a solvent. Thin-layer chromatography (TLC) was carried using silica gel F254 precoated plates. UV light and I2 stain were used to visualize the spots. Organic extracts and solutions of pure compounds were dried over anhydrous MgSO4. Single crystals of compounds 5a, 7a, and 7h were mounted on a MiTeGen loop with grease and examined on a Bruker D8 Venture APEX diffractometer equipped with a Photon 100 CCD area detector at 296 (2) K using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). Data were collected using APEX-II software,38 integrated using SAIN,39 and corrected for absorption using a multiscan approach (SADABS).40 Final cell constants were determined from full least squares refinement of all observed reflections. The structures were solved using intrinsic phasing (SHELXT).41 All non-H atoms were in subsequent difference maps and refined anisotropically. H-atoms were added at calculated positions and refined with a riding model. H atoms on O and N atoms were in a difference map and refined with constrained O–H and N–H distances. The structures of compounds 5a, 7a, and 7h have been deposited with the CCDC (CCDC deposition numbers = 2226650 (5a), 2226651 (7a), and 2226652 (7h)).

5.2. Knoevenagel General Procedure for the Synthesis of Compound 2

Meldrum’s acid (1.0 equiv) and p-anisaldehyde (1.0 equiv) were mixed in pyridine (0.1 M, 10 mL) and stirred at room temperature overnight under a nitrogen atmosphere. The resultant reaction mixture was dried, and the solids were either employed directly without additional purification or recrystallized in MeOH to produce pure compound 2 (97%).

5.2.1. 5-(4-Methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2)

Yellow solid (yellow color crystals); yield = 97%; m.p. 126–128 °C, 1H NMR (600 MHz, chloroform-d) δ 8.34 (s, 1H), 8.23–8.15 (m, 2H), 7.02–6.88 (m, 2H), 3.88 (d, J = 1.8 Hz, 3H), 1.76 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 164.6, 164.0, 160.4, 157.9, 137.6, 124.7, 114.3, 110.8, 104.1, 55.68, 27.49; HRMS (ESI+): found [M + Na]+: 285.0543 C14H14O5Na required 285.0541.

5.3. General Procedure for the Synthesis of Compound 3

A stirred solution of the Knoevenagel product (2, 1.0 equiv) suspended in absolute EtOH (0.1 M) received portions of sodium borohydride (2.0 equiv) during the course of 2 h. Upon completion, as determined by TLC, the reaction was quenched with 1 M aqueous HCl (15 mL/mmol), and the precipitate was filtered, washed with water, and dried at the pump to yield the desired compound without further purification or recrystallized in MeOH to yield pure compound 3 in a high yield (98%).

5.3.1. 5-(4-Methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (3)

White solid; yield = 98%; m.p. 83–85 °C, 1H NMR (600 MHz, chloroform-d) δ 7.24–7.16 (m, 2H), 6.84–6.73 (m, 2H), 3.74 (d, J = 1.9 Hz, 3H), 3.70 (dt, J = 4.8, 2.4 Hz, 1H), 3.43–3.37 (m, 2H), 1.69 (s, 3H), 1.45 (s, 3H); 3C NMR (150 MHz, CDCl3) δ 165.4, 158.7, 130.9, 129.0, 113.9, 105.1, 55.2, 48.2, 31.4, 28.4, 27.3; HRMS (ESI+): found [M + H]+: 265.0925 C14H17O5 required 265.0928.

5.4. General Procedure for the Synthesis of Compounds 5a and 5b

To a solution of compound 3 (1.0 equiv) in dry DMF (10 mL) were added successively anhydrous potassium carbonate (2.0 equiv) and propargyl bromide or benzyl bromide (1.1 equiv). The reaction mixture was stirred at room temperature for 18 h till completion of the reaction (monitored by TLC analysis). After completion of the reaction, it was extracted with EtOAc (3 × 30 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure on a rotary evaporator to furnish the desired compounds without further purification or recrystallized in EtOAc and DCM (1:1) solution to afford pure compounds 5a (98%) and 5b (96%), respectively.

5.4.1. 5-(4-Methoxybenzyl)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxane-4,6-dione (5a)

Light-green solid (light-green crystals from EtOAc and DCM (1:1) solution); yield = 98%; m.p. 146–148 °C, 1H NMR (600 MHz, chloroform-d) δ 7.04–6.93 (m, 2H), 6.80–6.70 (m, 2H), 3.69 (d, J = 1.9 Hz, 3H), 3.13 (s, 2H), 2.93 (t, J = 2.3 Hz, 2H), 2.10 (d, J = 5.2 Hz, 1H), 1.59 (s, 3H), 0.78 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 167.7, 159.4, 131.1, 126.2, 114.2, 106.5, 78.3, 72.9, 56.9, 55.2, 43.9, 30.2, 28.5, 28.1; HRMS (ESI+): found [M + H]+: 303.2076 C17H19O5 required 303.2074.

5.4.2. 5-Benzyl-5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (5b)

Light-yellow solid; yield = 96%; m.p. 142–145 °C, 1H NMR (600 MHz, chloroform-d) δ 7.21 (s, 2H), 7.18–7.16 (m, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.08–7.05 (m, 2H), 6.76–6.72 (m, 2H), 3.68 (d, J = 2.0 Hz, 3H), 3.36 (s, 2H), 3.33 (s, 2H), 0.65 (s, 3H), 0.58 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.2, 159.2, 134.9, 131.2, 130.1, 128.8, 127.7, 126.9, 114.1, 105.8, 60.2, 55.2, 44.8, 44.2, 28.7, 28.5; HRMS (ESI+): found [M + H]+: 355.1160 C21H22O5 required 355.1163.

5.5. General Procedure for the Synthesis of 1H-1,2,3-Triazol Derivatives of Meldrum’s Acid (7a–k)

CuI (2.0 equiv) and Et3N (3.0 equiv) were added to a solution of compound 5a (1.0 equiv) and substituted aromatic azides 6a–k (1.2 equiv) in acetonitrile (10 mL), and the mixture was stirred for three hours (3 h). The desired compounds were produced without the need for further purification by diluting the reaction mixture with EtOAc (30 mL), adding 20 mL of aqueous NH4Cl, extracting the aqueous layer with EtOAc (3 × 30 mL), washing the combined organic layer with brine (1 × 20 mL), drying it over anhydrous MgSO4, filtering it, and then concentrating it under reduced pressure on a rotary evaporator to furnish the desired compounds without further purification, or few compounds were recrystallized in EtOAc solution to afford pure 1H-1,2,3-triazol derivatives of Meldrum’s acid 7a–k in high yields (96–98%).

5.5.1. 5-(4-Methoxybenzyl)-2,2-dimethyl-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,3-dioxane-4,6-dione (7a)

Brown solid (brown crystals from EtOAc solvent); yield = 96%; m.p. 174–176 °C, 1H NMR (600 MHz, chloroform-d) δ 7.79 (s, 1H), 7.67–7.62 (m, 2H), 7.48 (dd, J = 8.6, 7.1 Hz, 2H), 7.43–7.38 (m, 1H), 7.16–7.12 (m, 2H), 6.83–6.79 (m, 2H), 3.74 (s, 3H), 3.63 (s, 2H), 3.38 (s, 2H), 1.39 (s, 3H), 0.72 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.2, 159.5, 142.5, 136.8, 131.4, 129.8, 128.9, 126.4, 120.6, 114.3, 106.8, 56.8, 55.3, 45.0, 34.2, 28.9, 28.6; HRMS (ESI+): found [M + H]+: 422.1734 C23H24N3O5 required 422.1732.

5.5.2. 5-(4-Methoxybenzyl)-2,2-dimethyl-5-((1-(o-tolyl)-1H-1,2,3-triazol-4-yl)methyl)-1,3-dioxane-4,6-dione (7b)

Red solid; yield = 98%; m.p. 146–148 °C, 1H NMR (600 MHz, chloroform-d) δ 7.61–7.39 (m, 1H), 7.33 (tq, J = 25.4, 8.7, 7.4 Hz, 3H), 7.24–7.01 (m, 3H), 6.80 (dq, J = 16.8, 10.2, 9.5 Hz, 2H), 3.74 (t, J = 7.7 Hz, 3H), 3.53–3.28 (m, 2H), 3.22–3.13 (m, 1H), 2.24–2.13 (m, 2H), 1.38 (d, J = 18.2 Hz, 2H), 1.30–1.17 (m, 3H), 0.71 (d, J = 12.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 168.2, 159.5, 141.6, 133.5, 131.4, 131.2, 126.8, 126.4, 125.8, 124.1, 114.3, 106.7, 57.0, 55.3, 44.9, 34.3, 28.9, 28.7, 28.5, 17.8; HRMS (ESI+): found [M + H]+: 436.1886 C24H26N3O5 required 436.1888.

5.5.3. 5-(4-Methoxybenzyl)-5-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7c)

Dark-brown solid; yield = 98%; m.p. 152–155 °C, 1H NMR (600 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.65 (dd, J = 7.7, 1.7 Hz, 1H), 7.38 (td, J = 7.9, 1.7 Hz, 1H), 7.15–7.12 (m, 2H), 7.04 (t, J = 7.9 Hz, 2H), 6.82–6.79 (m, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.63 (s, 2H), 3.38 (s, 2H), 1.34 (s, 3H), 0.72 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.2, 159.4, 151.1, 141.0, 131.3, 130.1, 126.5, 126.1, 125.4, 124.6, 121.1, 114.2, 112.1, 106.6, 57.1, 55.8, 55.3, 44.9, 34.3, 28.7, 28.6; HRMS (ESI+): found [M + H]+: 452.1841 C24H26N3O6 required 452.1843.

5.5.4. 5-(4-Methoxybenzyl)-2,2-dimethyl-5-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1,3-dioxane-4,6-dione (7d)

Red solid; yield = 96%; m.p. 154–57 °C, 1H NMR (600 MHz, chloroform-d) δ 7.83–7.79 (m, 1H), 7.72–7.61 (m, 3H), 7.43 (d, J = 7.8 Hz, 1H), 7.15–7.10 (m, 2H), 6.80 (dq, J = 8.6, 3.0 Hz, 2H), 3.73 (s, 3H), 3.62 (s, 2H), 3.38 (s, 2H), 1.35 (s, 3H), 0.71 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.1, 159.5, 141.8, 133.1, 131.4, 130.5, 128.9, 126.4, 125.5, 117.4, 114.3, 106.7, 57.1, 55.3, 45.0, 34.1, 28.9, 28.6; 19F NMR (564 MHz, chloroform-d) δ −59.1; HRMS (ESI+): found [M + H]+: 490.1624 C24H23F3N3O5 required 490.1626.

5.5.5. 5-(4-Methoxybenzyl)-5-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7e)

Light-brown solid; yield = 98%; m.p. 182–185 °C, 1H NMR (600 MHz, chloroform-d) δ 7.74 (s, 1H), 7.58–7.55 (m, 2H), 7.18–7.15 (m, 2H), 7.02–6.98 (m, 2H), 6.86–6.83 (m, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.65 (s, 2H), 3.41 (s, 2H), 1.43 (s, 3H), 0.75 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.1, 159.8, 159.4, 142.2, 131.3, 130.2, 126.4, 122.1, 120.7, 114.7, 114.2, 106.7, 56.7, 55.6, 55.2, 45.0, 34.1, 28.8, 28.6; HRMS (ESI+): found [M + H]+: 452.1831 C24H26N3O6 required 452.1828.

5.5.6. 5-(4-Methoxybenzyl)-2,2-dimethyl-5-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1,3-dioxane-4,6-dione (7f)

Dark-brown solid; yield = 96%; m.p. 142–145 °C, 1H NMR (600 MHz, chloroform-d) δ 7.94 (d, J = 1.9 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.68–7.61 (m, 2H), 7.15–7.10 (m, 2H), 6.84–6.79 (m, 2H), 3.74 (s, 3H), 3.63 (s, 2H), 3.38 (s, 2H), 1.42 (s, 3H), 0.72 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.1, 159.5, 137.1, 131.3, 130.5, 126.2, 125.4, 123.5, 120.5, 117.3, 114.3, 106.8, 56.5, 55.2, 45.0, 34.0, 28.8, 28.5; 19F NMR (564 MHz, chloroform-d) δ −62.87; HRMS (ESI+): found [M + H]+: 490.1592 C24H23F3N3O5 required 490.1594.

5.5.7. 5-((1-(3-Bromophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7g)

Red solid; yield = 97%; m.p. 176–179 °C, 1H NMR (600 MHz, chloroform-d) δ 7.89 (t, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.63 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 7.57 (ddd, J = 8.0, 1.9, 0.9 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.18–7.15 (m, 2H), 6.87–6.84 (m, 2H), 3.78 (s, 3H), 3.66 (s, 2H), 3.41 (s, 2H), 1.44 (s, 3H), 0.76 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.1, 159.5, 137.7, 131.9, 131.3, 131.1, 126.3, 123.6, 123.3, 119.0, 114.3, 106.9, 56.6, 55.3, 45.0, 34.1, 28.9, 28.6; HRMS (ESI+): found [M]+: 500.0711 C23H2279BrN3O5 required 500.0713. Found [M]+: 502.0694 C23H2281BrN3O5 required 502.0692.

5.5.8. 5-((1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7h)

Light-brown solid; yield = 97%; m.p. 178–181 °C, 1H NMR (600 MHz, chloroform-d) δ 7.78 (s, 1H), 7.61–7.57 (m, 2H), 7.55–7.52 (m, 2H), 7.12–7.09 (m, 2H), 6.81–6.78 (m, 2H), 3.72 (s, 3H), 3.60 (s, 2H), 3.36 (s, 2H), 1.38 (s, 3H), 0.70 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 168.1, 159.4, 135.7, 132.9, 131.3, 126.3, 122.5, 121.8, 120.4, 114.2, 106.8, 56.5, 55.3, 45.0, 34.0, 29.6, 28.8, 28.6; HRMS (ESI+): found [M]+: 500.0762 C23H2279BrN3O5 required 500.0760. Found [M]+: 502.0745 C23H2281BrN3O5 required 502.0748.

5.5.9. 5-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7i)

Light-green solid; yield = 96%; m.p. 184–186 °C, 1H NMR (600 MHz, chloroform-d) δ 7.77 (s, 1H), 7.62–7.56 (m, 2H), 7.47–7.41 (m, 2H), 7.13–7.09 (m, 2H), 6.82–6.78 (m, 2H), 3.73 (s, 3H), 3.60 (s, 2H), 3.36 (s, 2H), 1.39 (s, 3H), 0.71 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.1, 159.4, 142.8, 135.2, 134.6, 131.3, 129.9, 126.3, 121.6, 120.4, 114.2, 106.8, 56.5, 55.3, 45.0, 34.0, 28.8, 28.6; HRMS (ESI+): found [M + H]+: 456.1312 C23H23ClN3O5 required 456.1310.

5.5.10. 5-((1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7j)

Light-yellow solid; yield = 97%; m.p. 163–166 °C, 1H NMR (600 MHz, chloroform-d) δ 7.75 (s, 1H), 7.65–7.59 (m, 2H), 7.18–7.14 (m, 2H), 7.11 (s, 2H), 6.80 (d, J = 8.3 Hz, 2H), 3.73 (s, 3H), 3.61 (s, 2H), 3.36 (s, 2H), 1.40 (s, 3H), 0.71 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.1, 159.4, 142.7, 133.1, 131.3, 126.3, 122.5, 120.7, 116.8, 116.6, 114.2, 106.8, 56.5, 55.2, 45.0, 34.1, 29.6, 28.8, 28.6; 19F NMR (564 MHz, chloroform-d) δ −111.89; HRMS (ESI+): found [M + H]+: 440.1623 C23H23FN3O5 required 440.1625.

5.5.11. 5-(4-Methoxybenzyl)-2,2-dimethyl-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1,3-dioxane-4,6-dione (7k)

Light-brown solid; yield = 96%; m.p. 178–181 °C, 1H NMR (600 MHz, chloroform-d) δ 7.88 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.3 Hz, 2H), 3.73 (s, 3H), 3.62 (s, 2H), 3.37 (s, 2H), 1.40 (s, 3H), 0.71 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.0, 159.5, 143.1, 139.1, 131.3, 127.0, 126.2, 120.4, 114.2, 106.8, 56.5, 55.2, 45.0, 34.0, 29.6, 28.8, 28.5; 19F NMR (564 MHz, chloroform-d) δ −62.64; HRMS (ESI+): found [M + H]+: 490.1599 C24H23F3N3O5 required 490.1597.

5.6. α-Glucosidase Inhibition Assay

The recent studies were carried out using methodologies that we have previously published.42 The substrate P-nitro phenyl-α-d-glucopyranoside and enzyme α-glucosidase were dissolved in similar phosphate buffer (pH 6.8), and this buffer, 135 μL/well, was also employed in a 96-well plate as a reaction buffer. The tested compounds, 20 μL/well (0.5 mM) and 20 μL/well enzyme (0.02 U/well), were also added, followed by 15 min of incubation at 37 °C. On the completion of incubation time, 25 μL/well substrate p-nitro phenyl-α-d-glucopyranoside was loaded into a 96-well plate for 30 min; changes in absorbance owing to substrate degradation were observed at 400 nm. Acarbose was used as a positive control, and 7% DMSO served as a negative control. Later, statistical analysis was performed on SoftMax Pro suite and Excel to obtain the results for antidiabetic impact of the offered tested materials. The formula given below was used to calculate the percent inhibition of all the tested samples.

5.6. 1

For all the substances studied, EZ-FIT (Perrella Scientific, Inc., USA) was used to calculate IC50. All studies were done in triplicate to avoid predicted mistakes, and differences in the results are reported as standard error of mean values (SEM).

5.6. 2

5.7. Molecular Docking

The crystal structure of isomaltase from Saccharomyces cerevisiae in complex with its competitive inhibitor maltose (PDB code 3A4A)43 was taken for docking studies. In silico analysis was performed on Molecular Operating Environment (MOE version 2020.09),44 after validation of its docking protocol. The enzyme file was prepared for docking by adding missing hydrogen atoms and assigning partial charges according to MOE’s Amber10: EHT force field. The structures of the compounds were drawn on MOE and saved in the MOE compound database, where the saved structures were minimized using the same force field until the RMS gradient of 0.1 kcal/mol/Å was obtained. During the minimization process, partial charges were calculated automatically. The triangle matcher docking algorithm and London dG scoring function of MOE were used during ligand placement and scoring.

Acknowledgments

The University of Nizwa (UoN) provided kind funding for this endeavor, which the authors gratefully acknowledge. The Oman Research Council (TRC) financed the project through the funded project (BFP/RGP/CBS/21/006). The authors appreciate the help from the technical and analytical staff of the UoN.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c01291.

  • 1H-NMR 13C-NMR, 19F-NMR, and mass spectra of compounds 2, 3, 5a, 5b, and 7a–7k (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao3c01291_si_001.pdf (3.5MB, pdf)

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