Synthesis and evaluation of cinnamic acid derivatives as ɑ- glucosidase inhibitors

doi:10.21203/rs.3.rs-3996508/v1

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Synthesis and evaluation of cinnamic acid derivatives as ɑ- glucosidase inhibitors

https://doi.org/10.21203/rs.3.rs-3996508/v1

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Six cinnamic acid derivatives (1 ~ 6) were synthesized for finding potential α-glucosidase inhibitors. The structure of derivatives (1 ~ 6) were confirmed by NMR and HRMS. Inhibitory activity screening results showed that cinnamic acid derivatives (1 ~ 6) exhibited potential α-glucosidase inhibitory activity. Compound 2 showed the highest α-glucosidase inhibitory activity with IC₅₀ value of 39.91 ± 0.62 µM. SAR results showed that introduction of substituent groups in benzene ring of cinnamic acid enhanced the α-glucosidase inhibition activity, and methyl group had the optimal gain. Inhibitory kinetics results showed compound 2 was one reversible and mixed-type inhibitor. Molecular docking results revealed that compound 2 tightly bind to active pocket of α-glucosidase and formed hydrogen bond and hydrophobic interactions with α-glucosidase.

Cinnamic acid

Flavonoid

ɑ-Glucosidase

Inhibitor

Synthesis

Diabetes mellitus has been recognized as one of most prevailing chronic metabolic disorders. Hyperglycemia is the most importantly characteristics of diabetes mellitus [1–3]. As known that long term hyperglycemia status can cause some microvascular complications, such as cardiovascular disease and kidneys [4–6]. Effectively lowering hyperglycemia of diabetes patients has become an important measure to maintain their health. Lots researches have shown that hydrolysis of consumed carbohydrates is the main reasons for hyperglycemia [7–9].

α-Glucosidase is one of important hydrolase enzymes in body [10–12]. It locates on small intestine in human body and catalytic hydrolyzes carbohydrates as monosaccharides. Absorbing excess monosaccharides into blood leads to the postprandial hyperglycemia [13–14]. Thus, inhibiting α-glucosidase activity can effectively delay the hydrolysis of carbohydrates to control postprandial hyperglycemia [15–16]. As of now, numerous α-glucosidase inhibitors have been produced by scientists, in spite of few inhibitors have been used as clinical drugs, including acarbose, voglibose and miglitol [17–20]. Thus, finding more potential α-glucosidase inhibitors has become as one imperative work.

Cinnamic acid is one of important ingredients of Cinnamomum cassia Presl, existing wide activities, such as antioxidative, antibacterial, and anticancer, as well as its antidiabetic activities [21–22]. Lots researches have confirmed cinnamic acid as a potential α-glucosidase inhibitor. Moreover, lots cinnamic acid derivatives have synthesized as α-glucosidase inhibitors, including cinnamic acid amides and cinnamic acid esters (Fig. 1) [23–25]. Flavonoids are one kind of natural products abundantly exited in herbs and edible plants [26–27]. Flavonoids also present wide biological and pharmacological activities, including anti-α-glucosidase, anti-diabetic properties, antioxidants, and anti-inflammatory [28–30]. As dietary active ingredients, flavonoids have been getting more attention.

In the drug development process, structure modification of natural products is one important strategy to yield better biological activity compounds. Thence, in this study, cinnamic acid structure were modified using flavonoids to find potential α-glucosidase inhibitors.

2.1. Chemistry

Six cinnamic acid derivatives (1 ~ 6) were synthesized using substituted cinnamic acids according to Scheme 1. Firstly, p-hydroxybenzaldehyde underwent Claisen-Schmidt condensation with 2-hydroxyacetophenone to produce 4,2’-dihydroxychalcone, which was cyclized to yield 4’-hydroxyflavonoid. Finally, it underwent esterification with substituted cinnamic acids to obtain corresponding cinnamic acid derivatives (1 ~ 6), respectively. The structure of synthesized derivatives was identified by NMR and HRMS.

2.2. α-Glucosidase activity and SAR analysis

Six synthesized cinnamic acid derivatives (1 ~ 6) were firstly assayed for their α-glucosidase inhibitory activity. The inhibition of different concentration of derivatives (1 ~ 6) were assayed and then calculating their half inhibitory concentration values (IC₅₀), respectively. As shown in Table 1, six cinnamic acid derivatives (1 ~ 6) showed potential α-glucosidase inhibitory activity. Their IC₅₀ values ranged from 39.91 ± 0.62 to 65.23 ± 0.55 µM, comparing to control acarbose (634.28 ± 5.16 µM). Compound 2 presented the highest α-glucosidase inhibitory activity with IC₅₀ value of 39.91 ± 0.62 µM, ~ 16 times higher than acarbose. Thence, the synthesized cinnamic acid derivatives might be used as α-glucosidase inhibitors.

Talbe 1. The anti-α-glucosidase activity of cinnamic acid derivatives (1 ~ 6).

From the results in Table 1, the structure-activity relationship (SAR) was also analyzed to better guide future synthesis. Compound 1 had no substituent group in benzene ring of cinnamic acid showing IC₅₀ value of 65.23 ± 0.55 µM. Compared to compound 1, introduction of substituent groups in benzene ring of cinnamic acid enhanced the α-glucosidase inhibition activity, including methyl group, chlorine group, bromine group, fluorine group, and trifluoromethyl group (Fig. 2). Among them, methyl group had the optimal gain.

2.3. Inhibition kinetic

Nextly, we investigated the inhibition kinetic of compound 2 with the strongest inhibitory to study the inhibitory mechanisms. After detected the absorbance changes per minute of enzyme with different concentration in the present of compound 2, we got the plots of enzyme activity vs enzyme concentration (Fig. 3A). This plots all passed the origin, revealing compound 2 as a reversible inhibitor. Subsequently, we detected the absorbance changes per minute of substrate with different concentration in the present of compound 2, which yielded the Lineweaver-Burk plots of enzyme activity vs substrate concentration (Fig. 3B). This plots intersected at one point of second quadrant, indicating inhibition of compound 2 as a mix-type inhibition. In one word, compound 2 was a reversible mix-type inhibitor.

2.4. Molecular docking

Molecular docking between compound 2 and α-glucosidase was carried out using SYBYL software. Figure 4A showed the overall situation between between compound 2 and α-glucosidase, from which it could be seen that compound 2 reliably bind with the active pocket, and cinnamic acid section was at the exterior of active pocket. The detailed interactions between them were also investigated and showed that carbonyl of ester group formed a hydrogen bond with Asn 214 (3.3 Å) (Fig. 4B). Moreover, compound 2 formed hydrophobic interactions with Lys155, Ala278, His279, Val303, Phe311, and Gln350, respectively.

4.1 Materials and instruments

α-Glucosidase from Saccharomyces cerevisiae (EC 3.2.1.20) and p-Nitrophenyl-α-D-galactopyranoside (p-NPG) were purchased from Sigma-Aldrich. All other reagents were obtained from a commercial source. NMR spectra were obtained on 500 MHz equipment in CDCl₃. High-resolution mass spectral (HRMS) data was recorded on Apex II using the ESI technique.

4.2 Synthesis procedure of cinnamic acid derivatives (1 ~ 6)

To the 2-hydroxy acetophenone (10 mM) solution in piperidine (10 mL), appropriate benzaldehydes (10 mM) was added and reacted at 160°C until reaction was completed. Then reaction mixture was adjusted pH to 1 to yield precipitate, which was recrystallized using methanol to produce 4,2’-dihydroxychalcone. To the 4,2’-dihydroxychalcone (1 mM) solution in dimethyl sulfoxide, iodine (1 mM) was added and stirred at 100°C until reaction was completed, followed by treatment of 20% aqueous sodium thiosulfate and extraction with DCM. After DCM was evaporated, the obtained precipitate was recrystallized to obtain 4’-hydroxyflavonoid. To the 4’-hydroxyflavonoid (0.5 mM) solution in 10 ml DCM, substituted cinnamic acid (0.5 mM), DMAP (1 mM) and EDCI (1 mM) were added and reacted overnight. After the reaction was quenched with water, the mixture was extracted, washed, dried, and removed solvent under vacuum, followed by the purification using column chromatography to produce cinnamic acid derivatives (1 ~ 6), respectively.

(1, C₁₈H₁₃NO₄). White sold; Yield 72%; m.p. 157–159°C; ¹H NMR (500 MHz, Chloroform-d) δ 8.20 (s, 1H), 8.13 (dd, J = 8.1, 1.5 Hz, 2H), 7.66–7.57 (m, 3H), 7.51 (t, J = 7.7 Hz, 2H), 7.39–7.30 (m, 2H), 2.55 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 163.60, 162.71, 159.25, 154.37, 143.51, 133.67, 133.02, 129.76, 129.09, 128.71, 128.66, 124.98, 123.48, 118.53, 116.70, 77.33, 77.07, 76.82, 16.03; HRMS (ESI) [M + H]⁺ calcd. for C₁₈H₁₃NO₄:308.0914; found: 308.0926.

(2, C₁₉H₁₅NO₄). White sold; Yield 70%; m.p. 160–161°C; ¹H NMR (500 MHz, Chloroform-d) δ 8.20 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.35–7.28 (m, 3H), 2.55 (s, 3H), 2.44 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 163.76, 162.54, 159.21, 154.35, 144.86, 143.46, 133.06, 129.07, 128.47, 126.00, 125.97, 124.99, 123.42, 118.49, 117.96, 116.70, 77.32, 77.07, 76.81, 15.97; HRMS (ESI) [M + H]⁺ calcd. for C₁₉H₁₅NO₄: 322.1071; found:322.1084.

(3, C₁₈H₁₂ClNO₄). White sold; Yield 70%; m.p. 185–186°C; ¹H NMR (500 MHz, Chloroform-d) δ 8.19 (s, 1H), 8.06 (dd, J = 8.5, 1.6 Hz, 2H), 7.61–7.57 (m, 2H), 7.49 (dd, J = 8.4, 1.6 Hz, 2H), 7.39–7.31 (m, 2H), 2.55 (d, J = 1.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 162.98, 162.81, 159.23, 154.38, 143.59, 140.23, 133.12, 131.13, 129.12, 127.07, 125.02, 123.33, 118.48, 116.74, 77.31, 77.26, 77.05, 76.80, 16.09; HRMS (ESI) [M + H]⁺ calcd. for C₁₈H₁₂ClNO₄: 342.0525; found: 342.0536.

(4, C₁₈H₁₂BrNO₄). White sold; Yield 69%; m.p. 180–182°C; ¹H NMR (500 MHz, Chloroform-d) δ 8.18 (s, 1H), 8.00–7.97 (m, 2H), 7.66–7.64 (m, 2H), 7.62–7.57 (m, 2H), 7.38–7.31 (m, 2H), 2.54 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 163.01, 162.94, 159.20, 154.38, 143.58, 133.12, 132.11, 131.22, 129.11, 128.91, 127.53, 125.02, 123.31, 118.48, 116.73, 77.32, 77.07, 76.81, 16.08; HRMS (ESI) [M + H]⁺ calcd. for C₁₈H₁₂BrNO₄: 387.9997; found: 388.0004.

(5, C₁₈H₁₂FNO₄). White sold; Yield 68%; m.p. 208–209°C; ¹H NMR (500 MHz, Chloroform-d) δ 8.19 (s, 1H), 8.17–8.14 (m, 2H), 7.61–7.58 (m, 2H), 7.39–7.31 (m, 2H), 7.19 (t, J = 8.6 Hz, 2H), 2.55 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.17, 165.13, 162.82, 162.67, 159.23, 154.39, 143.54, 133.08, 132.41, 132.33, 129.10, 125.00, 124.89, 124.86, 123.38, 118.51, 116.73, 116.08, 115.90, 77.30, 77.25, 77.04, 76.79, 16.04; HRMS (ESI) [M + H]⁺ calcd. for C₁₈H₁₂FNO₄: 326.0820; found: 326.0832.

(6, C₁₉H₁₅NO₅). White sold; Yield 65%; m.p. 165–167°C; ¹H NMR (500 MHz, Chloroform-d) δ 8.20 (s, 1H), 8.10–8.08 (m, 2H), 7.59 (d, J = 7.7 Hz, 2H), 7.39–7.31 (m, 2H), 7.00–6.97 (m, 2H), 3.90 (s, 3H), 2.54 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 163.93, 163.38, 162.21, 159.33, 154.36, 143.45, 132.97, 131.90, 129.08, 124.97, 123.60, 120.79, 118.57, 116.70, 114.00, 77.30, 77.25, 77.05, 76.79, 55.56, 16.00; HRMS (ESI) [M + H]⁺ calcd. for C₁₉H₁₅NO₅: 338.1019; found: 338.1033.

4.3 a-Glucosidase inhibition and kinetics assay

Anti-α-glucosidase activity of cinnamic acid derivatives (1 ~ 6) was measured according to previous reports [31–32]. Test compound solution with different concentration was added into α-glucosidase solution and for 10 minutes, followed by the addition of p-NPG solution. The absorbance change of the mixture at 405 nm was measured. The inhibition rate of compound was calculated based on the absorbance change of blank α-glucosidase. Acarbose was used as a control.

Changing α-glucosidase concentration and fixing substrate concentration, the absorbance change α-glucosidase in the presence of compound 2 was measured. The obtained plots could be used to analyze the enzyme kinetic [33–34]. Similarly, fixing α-glucosidase concentration and changing substrate concentration, the absorbance change α-glucosidase in the presence of compound 2 was measured, thereby obtained Lineweaver-Burk plots could be used to analyze the substrate kinetic [35–36].

4.4. Molecular docking

Molecular docking was simulated using SYBYL to investigate the binding of compound 2 with α-glucosidase according to previous reports [37–38]. Compound 2 structure was firstly built and treated with energy minimization. The homologous model of α-glucosidase was built and treated with hydrogenation and rehabilitation disability [39–40]. Finally, the docking between compound 2 and α-glucosidase was carried out in default format.

Conflict of Interest

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.

Author Contributions

Hua Zhu carried out the investigation, and Xin Zhong was responsible for project design.

Funding

This work was financially supported by the Start Fund Project of Mianyang Teacher’s College (Nos. QD2020A01).

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Scheme 1 is available in the Supplementary Files section.

No competing interests reported.

Scheme1.jpg
Scheme 1. Synthesis of cinnamic acid derivatives (1~6). Reagents and condition: (a) Piperdine, reflux, 160 °C; DMSO, I₂, 100 °C; (b) Substituted cinnamic acid, DMSO, EDCI, DCM, rt.
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Synthesis and evaluation of cinnamic acid derivatives as ɑ- glucosidase inhibitors

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Abstract

Figures

1. Introduction

2. Results and Discussion

2.1. Chemistry

2.2. α-Glucosidase activity and SAR analysis

2.3. Inhibition kinetic

2.4. Molecular docking

3. Conclusion

4. Experimental

4.1 Materials and instruments

4.2 Synthesis procedure of cinnamic acid derivatives (1 ~ 6)

4.3 a-Glucosidase inhibition and kinetics assay

4.4. Molecular docking

Declarations

References

Scheme 1

Additional Declarations

Supplementary Files

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