Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: Design, synthesis, in vitro α-glucosidase inhibition, and computational studies

doi:10.21203/rs.3.rs-2218501/v1

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Research Article

Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: Design, synthesis, in vitro α-glucosidase inhibition, and computational studies

https://doi.org/10.21203/rs.3.rs-2218501/v1

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published 15 Jun, 2023

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Background

A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a-o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase.

Methods

The fifteen various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted.

Results

All new derivatives 11a-o (IC₅₀ values = 6.31 ± 0.03–49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC₅₀ value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC₅₀ = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound.

Conclusion

According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.

Diabetes mellitus (DM) is a set of metabolic disease characterized by hyperglycemia [1]. This disorder mainly induced by the deficiency of insulin production or function [2]. DM led to vessels damages and becomes the cause of failure in many organs such as heart, kidneys, nerves, and the eyes [3]. The most common type of DM is type 2 diabetes (T2DM), which is usually associated with incomplete function of insulin [4]. According to the World Health Organization reports, the number of patients with T2DM will reach 360 million by 2030. The essential goal of treatment of T2DM is blood glucose level control, particularly after a meal [5]. In this regard, one effective strategy is to prevent the breakdown of the food carbohydrates into glucose. One of the most important enzymes for breaking down carbohydrates into glucose is α-glucosidase. Therefore, an important group of anti-diabetic drugs are α-glucosidase inhibitors [6]. The most common and commercially available α-glucosidase inhibitors are acarbose, voglibose, and miglitol [7]. Some studies show that use of these drugs is associated with gastrointestinal complications including diarrhea, bloating, and abdominal panic [8]. Therefore, design and development of new efficient and potent α-glucosidase inhibitors with at least side effects are interest goals to medicinal chemists [9].

Indole is a bicyclic N-heterocycle with various biological effects such as antimicrobial, antiviral, anticancer, anticonvulsant, antitubercular, and antimalarial properties [10–14]. In addition to, this ring has attracted much attention as a privileged pharmacophore for design of new potent α-glucosidase inhibitors [15]. During the recent years, several series of natural and synthetic indole derivatives with significant anti-α-glucosidase activity have been reported [15]. One of this effective synthetic series are indole-carbohydrazide derivatives A that most potent compound in this series inhibited α-glucosidase around 394-fold more that positive control acarbose (Fig. 1) [16]. Another pharmacophore that has recently received attention in the design of α-glucosidase inhibitors is phenoxy-1,2,3-triazole-N-phenylacetamide moiety [17]. As can be seen Fig. 1, this moiety is observed in potent α-glucosidase inhibitors B (IC₅₀ values = 25.2 ± 0.9-176.5 ± 6.7 µM comparing with acarbose, 750.0 ± 12.5 µM) [18].

Based on the reported potent α-glucosidase inhibitors A and B, respectively, containing indole-carbohydrazide and phenoxy-1,2,3-triazole-N-phenylacetamide moieties, we designed indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold in order to achieve new potent α-glucosidase inhibitors 11 (Fig. 1). Therefore, we synthesized fifteen derivatives of this scaffold and evaluate them for their in vitro α-glucosidase inhibition effects. Furthermore, in vitro kinetic analysis and in silico molecular docking study were used to elucidate the interaction between the newly synthesized compounds and α-glucosidase. Lastly, pharmacokinetic and toxicity of these compounds were predicted by a reliable online software.

Chemistry

The desired indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 11a-o were prepared in good yields as shown in Scheme 1. The preparation of target compounds 11a-o was started from conversion of indole-2-carboxylic acid 1 to methyl 1H-indole-2-carboxylate 2 in the presence of sulfuric acid in methanol. The obtained ester 2 was converted to 1H-indole-2-carbohydrazide 3 in the presence of hydrazine in ethanol. On the other hand, 4-(prop-2-ynyloxy)benzaldehydes 6a-b were produced by a reaction between 4-hydroxy-benzaldehyde derivatives 4a-b and propargyl bromide 5 in the presence of K₂CO₃ in DMF at room temperature. N-phenyl-2-chloroacetamide derivatives 9a-k were prepared by the reaction between aniline derivatives 7a-k and chloroacetyl chloride 8 in DMF at room temperature. Compounds 6a-b and 9a-k produce compounds 10a-o during two reaction steps (click reaction): accordingly, various chloride derivatives 9a-k and sodium azide were reacted in the mixture of H₂O and t-BuOH (1:1) in the presence of Et₃N at room temperature and after that, a mixture of compounds 6a-b, sodium ascorbate, and CuSO₄.5H₂O was added to azide mixture and the reaction was continued at room temperature to afford the 1,2,3-triazole derivatives 10a-o. Finally, 1H-indole-2-carbohydrazide 3 were reacted with 1,2,3-triazole derivatives 10a-o in the presence of acetic acid in ethanol for give target compounds 11a-o.

In vitro anti-α-glucosidase activity and SAR discussion

The in vitro anti-α-glucosidase activity of the new indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 11a-o was evaluated by using standard method as described earlier [19]. Acarbose was chosen as standard drug and enzyme inhibition activities are expressed as IC₅₀ values in Table 1. As evidenced by obtained IC₅₀ values, both phenoxy derivatives 11a-h and 2-methoxyphenoxy derivatives 11i-o showed excellent anti-α-glucosidase activity. These compounds with IC₅₀ values ranging from 6.31 ± 0.03 to 49.89 ± 0.09 µM are promising α-glucosidase inhibitors when compared to acarbose with IC₅₀ value of 750.0 ± 10.0 µM.

Compound	R¹	R²	IC₅₀ (µM)
11a	H	H	15.21 ± 0.18
11b	H	2-CH₃	8.88 ± 0.07
11c	H	4-CH₃	19.12 ± 0.08
11d	H	4-OCH₃	6.31 ± 0.03
11e	H	2-Cl	26.97 ± 0.25
11f	H	4-Cl	9.53 ± 0.12
11g	H	4-Br	49.89 ± 0.09
11h	H	4-NO₂-3-CH₃	35.11 ± 0.07
11i	OCH₃	H	11.25 ± 0.15
11j	OCH₃	4-OCH₃	24.19 ± 0.1
11k	OCH₃	4-Cl	31.56 ± 0.12
11l	OCH₃	2,3-Dichloro	18.2 ± 0.81
11m	OCH₃	3,5-Dichloro	14.2 ± 0.21
11n	OCH₃	4-Br	8.3 ± 0.16
11o	OCH₃	2-Cl-3-NO₂	12.67 ± 0.05
Acarbose	-	-	750.0 ± 10.0

Among the synthesized compounds, the N-4-methoxyphenylacetamide derivative 11d from phenoxy series was the most potent entry. The latter compound was 118.8 times more potent than acarbose. Replacement of methoxy substituent of compound 11d with chloro, methyl, and or bromo substituents, as in the case of compounds 11f, 11c, and 11g, the inhibitory activity diminished to 1.5, 3, and 8 folds, respectively. A survey on the structures and inhibitory activities in Table 1 demonstrated that in phenoxy series (compounds 11a-h), the chloro substituent had the best effect in 4-position of N-arylacetamide moiety (compound 11f vs. compound 11e) while methyl substituent had the best effect in 2-position of the latter moiety (compound 11b vs. compound 11c).

Moreover, the comparison of inhibitory activity of the substituted compounds 11b-h with un-substituented compounds 11a was depicted in Fig. 2. This figure showed that introduction of 4-methoxy, 2-methyl, and 2-chloro substituents on phenyl ring of N-arylacetamide moiety improved inhibitory activity in comparison to un-substituted compound 11a while the presence of 4-methyl, 2-chloro, 4-nitro-3-methyl, and 4-bromo substituents deteriorated inhibitory activity. The weakest inhibitor in this series was 4-bromo derivative 11g.

In the 2-methoxyphenoxy series (compounds 11i-o), unlike the first series, the most potent agent was 4-bromo derivative 11n. The second potent compound in this series was un-substituted compound 11i. Introduction of 2-Cl-3-NO₂, 3,5-dichloro, 2,3-dichloro, 4-OCH₃, or 4-Cl deteriorated inhibitory activity in comparison to un-substituted compound 11i (Fig. 3). The weakest inhibitor in 2-methoxyphenoxy series was 4-chloro derivative 11g.

The comparison of IC₅₀ values of phenoxy derivatives with their corresponding 2-methoxyphenoxy analogs revealed that phenoxy analogs with 4-methoxy (compound 11d) and 4-chloro (compound 11f) were more active than their 2-methoxyphenoxy analogs (compounds 11j and 11k, respectively) while 2-methoxyphenoxy analogs with un-substituented phenyl (compound 11i) and 4-bromophenyl (compound 11n) were more potent of their corresponding analogs of phenoxy series (compounds 11a and 11g, respectively).

On the other hand, the comparison of IC₅₀ values of the new indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 11 with their corresponding analogs of benzimidazole-phenoxy-1,2,3-triazole-N-phenylacetamide series B revealed that replacement of indole-carbohydrazide moiety instead of benzimidazole ring led to a significant increase in inhibitory activity as observed in Fig. 4 [18].

To determine the mechanism of α-glucosidase inhibition of the newly synthesized compounds, the kinetic studies were performed on the most potent compounds 11d, 11n, and 11b as representative compounds. To construct the Lineweaver-Burk plots, enzymatic reactions were performed in the four concentrations of substrate and inhibitors: p-nitrophenyl-glucopyranoside as substrate in concentrations 1–4 mM, compound 11d at concentrations: 0, 1.25, 2.5 and 5 µM and compounds 11n and 11b at concentrations: 0, 2.5, 5 and 10 µM as inhibitors. Then, the Lineweaver-Burke plots were depicted using by the reciprocal of velocity and substrate concentration (Fig. 5). Lineweaver-Burk plots of the studied compounds demonstrated that in the presence of compounds 11d, 11n, and 11b both V_max and K_m values were decreased. Therefore, the latter compounds are uncompetitive inhibitors. Using by the Lineweaver-Burk secondary plot (Fig. 5), K_i values equal to 6.3, 8.3, and 8.5 µM were determined for compounds 11d, 11n, and 11b, respectively.

Additionally to the SAR evaluation based on in vitro data, we performed an in silico docking study on the most potent compounds 11d and 11n. Crystal structure of the S. cerevisiae α-glucosidase was not available in the protein data bank, thus, we used of a modeled enzyme based on previous works [19]. Docking study of positive control acarbose demonstrated that this drug formed following interactions in the α-glucosidase active with binding energy of -4.04 Kcal/mol:

1) Hydrogen bonds with Thr301, Gln322, Thr307, Arg312, Glu304, Ser308, Asn241

2) Non-classical hydrogen bond with His239

3) Hydrophobic interaction with His279

4) Unfavorable interactions with Arg312 and Thr207.

As can be seen Fig. 6, the most active derivative 11d established hydrogen bonds with active site residues Gly306, Thr307, Phe157, and Tyr313. Compound 11d formed two π-anion interactions with Asp408. Several hydrophobic interactions were also observed between compound 11d and residues Pro309, Ser308, and Arg312. In addition, this compound formed three non-classical hydrogen bonds with Glu304, Thr307, and His239. Interaction mode of the second potent compound 11n demonstrated that this compound formed classical hydrogen bonds with residues Thr301 and Phe157 and non-classical hydrogen bonds with Thr301, Ser308, and His239 (Fig. 6). Furthermore, this compound also created a π-anion interaction (Glu304) and several hydrophobic interactions (Val305, Val316, Pro309, Phe300, and Arg312) with the active site.

(11d)	(11n)

Figure 6. Interaction modes of the most potent compounds 11d and 11n in the active site of α-glucosidase.

Binding energies, type of interactions, interacting unit of the compounds 11d and 11n, and involved amino acids in the interactions were listed in Table 2. As can be seen in this table, binding energy values of these compounds were lower than acarbose. On the other hand, the first potent compound 11d had binding energy value lower than the second potent compound 11n. These results are in agreement with the obtained results from in vitro enzymatic inhibition assay.

Table 2

Interaction mode details of the most potent compounds **11d** and **11n**.
Compound	Binding energy	Interaction	Interacting unit of the ligand	Amino acid
11d	-9.01	H-bond	NH-CO	Gly306
		Hydrophobic	1,2,3-triazol	Pro309
		Hydrophobic	1,2,3-triazol	Ser308
		H-bond	O of phenoxy linker	Thr307
		Hydrophobic	Phenyl of phenoxy linker	Arg312
		H-bond	C = N-NH-CO	Tyr313
		Hydrophobic	Indole	Arg312
		π-Anion	Indole	Asp408
11n	-8.96	Hydrophobic	4-Br	Val316
		Hydrophobic	Pendant phenyl	Val305
		H-bond	NH-CO	Thr301
		Hydrophobic	1,2,3-triazol	Pro309
		π-Anion	1,2,3-triazol	Glu304
		Hydrophobic	Phenyl of phenoxy linker	Arg312
		H-bond	C = N-NH-CO	Phe157
		Hydrophobic	Indole	Phe300

In silico pharmacokinetic and toxicity studies

Pharmacokinetic and toxicity predictions of acarbose and the most potent compounds 11d and 11n were performed by PreADMET online software and the obtained results were listed in Table 3 [20]. As can be seen in this table, positive control acarbos did not follow of Lipinski 'Rule of five' while compounds 11d and 11n followed of this rule. All studied compounds acarbose, 11d, and 11n had poor permeability to Caco-2. Permeability to blood brain barrier (BBB) and skin for these compounds is in the acceptable range. Compounds 11d and 11n had high human intestinal absorption (HIA) while acarbose did not have HIA. In silico toxicity prediction demonstrated that acarbose and compound 11d are mutagen while compound 11n is not mutagen. Moreover, this study predicted that acarbose and compound 11d had carcinogenic effect on mouse and did not have this effect on rat while compound 11n has carcinogenic effect on rat and did not have carcinogenic effect mouse. Cardiotoxicity (hERG inhibition) of acarbose is ambiguous while compounds 11d and 11n in term of this type of toxicity have high risk.

Table 3

Druglikeness/ADME/T profile of acarbose and the most potent compounds **11d** and **11n**.
Druglikeness/ADME/T ^a	Compound
Druglikeness/ADME/T ^a	Acarbose	11d	11n
Rule of Five	Violated	Suitable	Suitable
Caco2	9.44448	3.03438	18.8466
HIA	0.000000	91.952780	94.030638
BBB	0.0271005	0.272919	0.411249
Skin permeability	-5.17615	-3.52204	-3.34921
Ames test	Mutagen	Mutagen	Non-mutagen
Carcino mouse	Positive	Positive	Negative
Carcino rat	Negative	Negative	Positive
hERG inhibition	Ambiguous	High risk	High risk
^a The recommended ranges for Caco2: <25 poor, > 500 great, HIA: >80% is high < 25% is poor, BBB = − 3.0–1.2, and Skin_Permeability = − 8.0 – − 1.0.

Synthesis of methyl 1 H -indole-2-carboxylate 2

A mixture of indole-2-carboxylic acid 1 (10 mmol), sulfuric acid (2 mL), and methanol (20 mL) was heated under reflux condition for 12 h. Then, cold water was added to the latter mixture reaction and the obtained mixture was extracted by ethyl acetate. The ethyl acetate was evaporated under reduced pressure to produce pure methyl 1H-indole-2-carboxylate 2.

Synthesis of 1 H -indole-2-carbohydrazide 3

A solution of methyl 1H-indole-2-carboxylate 2 (3 mmol) and hydrazine (9 mmol) in ethanol (20 mL) was stirred at room temperature for 6 h. Then, with adding water to the mixture reaction, the white precipitates of 1H-indole-2-carbohydrazide 3 as final product in this step were appeared and separated by filtration.

A suspension of 4-hydroxy-3-methoxybenzaldehydes 4a-b (1 mmol) and K₂CO₃ (1 mmol) in DMF (10 ml) was stirred at room temperature for 1 h. After that, the obtained suspension was added to a solution of propargyl bromide 5 (1.2 mmol) in DMF (5 ml) in a dropwise manner, and the reaction mixture was stirred at room temperature for 2 h. Then, the reaction mixture was poured into crushed ice, and the final mixture was filtered off and residue was recrystallized in ethanol to obtain 3-methoxy-4-(prop-2-ynyloxy) benzaldehydes 6a-b.

General procedure for the synthesis of N-phenyl-2-chloroacetamide derivatives 9a-k

Aniline derivatives 7a-k and chloroacetyl chloride 8 in DMF were stirred at room temperature for 30 min. At the end of the reaction (checked by TLC), the reaction mixture was diluted with cold water, poured into crushed ice, and the obtained white precipitates were filtered off. The residues were washed with water to obtain pure N-phenyl-2-chloroacetamides 9a-k.

General procedure for the synthesis of indole-carbohydrazide-phenoxy-1,2,3-triazole- N -phenylacetamide derivatives 11a-o

At first, 1,2,3-triazol derivatives 10a-o were prepared. For this purpose, a mixture of N-phenyl-2-chloroacetamides 9a-k (1.1 mmol), sodium azide (0.9 mmol), and Et₃N (1.3 mmol) in the mixture of water plus t-BuOH (10 mL, 1:1) was stirred at room temperature for 1 h. Then, a mixture of 4-(prop-2-ynyloxy)benzaldehydes 6a-b (1 mmol), sodium ascorbate, and CuSO₄.5H₂O (7 mol %) was added to the pervious mixture, and obtained mixture was stirred at room temperature for 24–48 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and poured into ice. Then, precipitated products 10a-o were filtered off, washed with water, and purified by recrystallization in ethanol. Finally, a mixture of the latter compounds (1 mmol) and 1H-indole-2-carbohydrazide 3 (1 mmol), and acetic acid (3 drops) in ethanol (20 mL) was stirred at room temperature for 6 h. After that, water was added to the latter mixture and pure precipitated products 11a-o were filtered off.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -phenylacetamide (11a)

White solid; isolated yield: 83%, mp: 194–196°C; IR (KBr, υ): 3287, 3059, 1669 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.89–11.64 (m, 2H), 10.53 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 7.4 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.39–7.32 (m, 3H), 7.25–7.16 (m, 3H), 7.14–7.08 (m, 2H), 5.41 (s, 2H, N-CH₂), 5.29 (s, 2H, O-CH₂); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.65, 160.08, 158.00, 147.50, 142.72, 139.65, 138.89, 137.27, 130.68, 130.52, 129.39, 129.15, 128.63, 126.90, 126.00, 124.26, 122.22, 120.41, 115.60, 112.86, 103.93, 61.66, 52.74; Anal Calcd for C₂₇H₂₃N₇O₃, C, 65.71, H, 4.70, N, 19.87; Found: C, 65.72, H, 4.67, N, 19.80.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(o-tolyl)acetamide (11b)

White solid; isolated yield: 89%, mp: 208–210°C; IR (KBr, υ): 3281, 3057, 1666 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.91–11.80 (m, 2H), 10.45 (s, 1H), 8.33 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 3H), 7.47–7.40 (m, 1H), 7.40–7.34 (m, 1H), 7.32–7.22 (m, 3H), 7.21–7.00 (m, 4H), 5.39 (s, 2H, N-CH₂), 5.26 (s, 2H, O-CH₂), 2.27 (s, 3H, CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.39, 162.77, 158.06, 149.77, 147.97, 137.30, 136.37, 133.26, 129.77, 128.64, 127.95, 127.52, 126.02, 124.29, 122.29, 122.22, 120.45, 119.73, 113.46, 112.97, 112.88, 108.88, 104.00, 55.88, 36.24, 20.92; Anal Calcd for C₂₈H₂₅N₇O₃, C, 66.26, H, 4.96, N, 19.32; Found: C, 66.27, H, 4.90, N, 19.37.

( E )-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(p-tolyl)acetamide (11c)

White solid; isolated yield: 93%, mp: 180–182°C; IR (KBr, υ): 3280, 3055, 1669 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.87–11.64 (m, 2H), 10.44 (s, 1H), 8.51–8.40 (m, 1H), 8.33 (s, 1H), 7.79–7.68 (m, 3H), 7.54–7.48 (m, 3H), 7.39–7.32 (m, 1H), 7.26 (d, J = 7.0 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H), 7.19–7.06 (m, 4H), 5.39 (s, 2H, N-CH₂), 5.29 (s, 2H, O-CH₂), 2.27 (s, 3H, CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.38, 160.09, 158.02, 147.49, 137.28, 136.37, 133.26, 130.76, 129.77, 129.16, 128.62, 127.69, 127.51, 126.90, 124.26, 122.21, 120.42, 119.73, 115.60, 112.87, 103.90, 61.66, 56.54, 20.92; Anal Calcd for C₂₈H₂₅N₇O₃, C, 66.26, H, 4.96, N, 19.32; Found: C, 66.20, H, 4.99, N, 19.37.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(4-methoxyphenyl)acetamide (11d)

White solid; isolated yield: 90%, mp: 229–231°C; IR (KBr, υ): 3284, 3052, 1669 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.85–11.60 (m, 2H), 10.38 (s, 1H), 8.50–8.39 (m, 1H), 8.32 (s, 1H), 7.80–7.68 (m, 3H), 7.56–7.49 (m, 3H), 7.38–7.31 (m, 1H), 7.28–7.18 (m, 3H), 7.10 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H), 5.37 (s, 2H, N-CH₂), 5.29 (s, 2H, O-CH₂), 3.75 (s, 3H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.11, 160.09, 158.03, 156.05, 147.49, 142.71, 137.28, 131.98, 130.69, 129.16, 127.70, 127.53, 126.86, 124.26, 122.22, 121.30, 120.41, 115.61, 114.51, 112.87, 103.89, 61.68, 55.65, 52.67; Anal Calcd for C₂₈H₂₅N₇O₄, C, 64.24, H, 4.81, N, 18.73; Found: C, 64.20, H, 4.85, N, 18.75.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-chlorophenyl)acetamide (11e)

White solid; isolated yield: 85%, mp > 250°C; IR (KBr, υ): 3288, 3053, 1668 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 13.00–12.91 (m, 2H), 11.81–11.53 (m, 1H), 8.34 (s, 1H), 8.30–8.25 (m, 1H), 7.72–7.66 (m, 4H), 7.54 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.25–7.16 (m, 3H), 7.01–6.96 (m, 1H), 6.73 (s, 1H), 5.48 (s, 2H, N-CH₂), 5.34 (s, 2H, O-CH₂); ¹³C NMR (76 MHz, DMSO-d₆) δ 167.70, 167.66, 159.15, 155.62, 146.38, 144.68, 143.12, 139.65, 136.97, 134.92, 132.98, 132.52, 130.52, 129.63, 127.17, 126.62, 126.40, 122.24, 121.64, 121.28, 116.36, 115.17, 113.68, 62.01, 50.93; Anal Calcd for C₂₇H₂₂ClN₇O₃, C, 61.42, H, 4.20, N, 18.57; Found: C, 61.44, H, 4.27, N, 18.51.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(4-chlorophenyl)acetamide (11f)

White solid; isolated yield: 91%, mp: 174–176°C; IR (KBr, υ): 3281, 3059, 1667 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.87–11.62 (m, 2H), 10.67 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.71–7.59 (m, 3H), 7.50 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.35 (s, 1H), 7.26 (d, J = 7.0 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 7.7 Hz, 1H), 5.41 (s, 2H, N-CH₂), 5.29 (s, 2H, O-CH₂); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.86, 160.07, 158.02, 147.47, 142.75, 137.83, 137.29, 130.69, 129.33, 129.16, 127.88, 127.70, 127.51, 126.90, 125.99, 124.25, 122.21, 120.41, 115.60, 112.86, 103.89, 61.65, 56.53, 21.25; Anal Calcd for C₂₇H₂₂ClN₇O₃, C, 61.42, H, 4.20, N, 18.57; Found: C, 61.44, H, 4.18, N, 18.63.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(4-bromophenyl)acetamide (11g)

White solid; isolated yield: 83%, mp: 239–241°C; IR (KBr, υ): 3288, 3052, 1668 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.92–11.61 (m, 2H), 10.67 (s, 1H), 8.50–8.42 (m, 1H), 8.33 (s, 1H), 7.78–7.68 (m, 3H), 7.62–7.50 (m, 5H), 7.39–7.33 (m, 1H), 7.26 (d, J = 7.0 Hz, 1H), 7.23–7.17 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 5.42 (s, 2H, N-CH₂), 5.29 (s, 2H, O-CH₂); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.88, 162.77, 160.08, 158.05, 147.51, 142.76, 138.24, 137.29, 132.23, 130.70, 129.16, 127.71, 127.53, 126.89, 124.27, 122.22, 121.68, 120.42, 115.94, 115.60, 112.87, 61.67, 52.75; Anal Calcd for C₂₇H₂₂BrN₇O₃, C, 56.65, H, 3.87, N, 17.13; Found: C, 56.64, H, 3.80, N, 17.15.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)phenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(3-methyl-4-nitrophenyl)acetamide (11h)

White solid; isolated yield: 82%, mp: 200–202°C; IR (KBr, υ): 3291, 3057, 1668 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.91–11.63 (m, 2H), 10.12 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 8.15 (d, J = 2.7 Hz, 1H), 8.08 (dd, J = 8.9, 2.7 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.78–7.72 (m, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.55–7.50 (m, 1H), 7.42–7.35 (m, 1H), 7.29–7.23 (m, 1H), 7.21 (d, J = 6.6 Hz, 1H), 7.12 (d, J = 4.7 Hz, 1H), 7.10–7.04 (m, 1H), 5.60 (s, 2H, N-CH₂), 5.29 (s, 2H, O-CH₂), 2.43 (s, 3H, CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 167.66, 160.07, 158.12, 145.48, 143.94, 142.83, 142.58, 138.65, 137.31, 129.17, 128.72, 127.71, 127.54, 126.95, 126.01, 125.98, 124.28, 120.83, 120.43, 115.57, 115.16, 112.88, 104.04, 61.65, 52.72, 21.22; Anal Calcd for C₂₈H₂₄N₈O₅, C, 60.86, H, 4.38, N, 20.28; Found: C, 60.88, H, 4.45, N, 20.25.

White solid; isolated yield: 91%, mp: 204–206°C; IR (KBr, υ): 3294, 3051, 1667 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.91–11.70 (m, 2H), 10.53 (s, 1H), 8.48–8.42 (m, 1H), 8.33 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.44–7.40 (m, 1H), 7.40–7.33 (m, 3H), 7.33–7.27 (m, 2H), 7.26–7.22 (m, 1H), 7.14–7.07 (m, 2H), 5.41 (s, 2H, N-CH₂), 5.26 (s, 2H, O-CH₂), 3.85 (s, 3H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.66, 158.03, 149.92, 149.78, 147.91, 142.69, 138.89, 137.30, 130.67, 129.40, 127.96, 127.51, 127.03, 124.27, 122.23, 120.43, 119.72, 113.50, 112.88, 108.93, 103.96, 62.06, 55.90, 52.73; Anal Calcd for C₂₈H₂₅N₇O₄, C, 64.24, H, 4.81, N, 18.73; Found: C, 64.27, H, 4.80, N, 18.78.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)-2-methoxyphenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(4-methoxyphenyl)acetamide (11j)

White solid; isolated yield: 92%, mp: 214–216°C; IR (KBr, υ): 3290, 3054, 1669 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 12.02–11.62 (m, 2H), 10.70 (s, 1H), 8.53–8.39 (m, 1H), 8.32 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.62–7.50 (m, 6H), 7.43 (d, J = 4.5 Hz, 1H), 7.40–7.33 (m, 1H), 7.31–7.28 (m, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 5.42 (s, 2H, N-CH₂), 5.26 (s, 2H, O-CH₂), 3.84 (s, 6H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.10, 156.03, 153.36, 149.91, 149.77, 138.54, 131.97, 130.38, 128.70, 127.98, 127.37, 127.15, 126.32, 126.02, 122.22, 121.28, 120.42, 114.48, 113.65, 112.99, 112.87, 110.15, 108.86, 62.17, 62.08, 55.93, 55.89; Anal Calcd for C₂₉H₂₇N₇O₅, C, 62.92, H, 4.92, N, 17.71; Found: C, 62.95, H, 4.97, N, 17.68.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)-2-methoxyphenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(4-chlorophenyl)acetamide (11k)

White solid; isolated yield: 88%, mp: 184–186°C; IR (KBr, υ): 3293, 3051, 1668 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.91–11.63 (m, 2H), 10.66 (s, 1H), 8.57–8.37 (m, 1H), 8.33 (s, 1H), 7.72–7.63 (m, 3H), 7.52 (d, J = 8.2 Hz, 1H), 7.45–7.34 (m, 4H), 7.33–7.21 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H), 5.42 (s, 2H, N-CH₂), 5.26 (s, 2H, O-CH₂), 3.85 (s, 3H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.87, 162.77, 158.05, 149.91, 149.78, 147.92, 140.66, 137.83, 137.30, 130.69, 129.32, 127.98, 127.90, 127.52, 127.07, 124.28, 122.62, 122.23, 120.43, 113.52, 112.88, 108.97, 103.99, 62.07, 52.72, 36.24; Anal Calcd for C₂₈H₂₄ClN₇O₄, C, 60.27, H, 4.34, N, 17.57; Found: C, 60.20, H, 4.37, N, 17.59.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)-2-methoxyphenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2,3-dichlorophenyl)acetamide (11l)

White solid; isolated yield: 91%, mp: 181–183°C; IR (KBr, υ): 3287, 3051, 1668 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.87–11.59 (m, 2H), 10.29 (s, 1H), 8.49–8.43 (m, 1H), 8.34 (s, 1H), 7.79–7.69 (m, 4H), 7.54–7.48 (m, 2H), 7.37–7.32 (m, 1H), 7.27–7.22 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.13–7.07 (m, 1H), 5.55 (s, 2H, N-CH₂), 5.29 (s, 2H, O-CH₂), 3.88 (s, 3H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 165.56, 160.07, 158.06, 147.51, 142.80, 137.29, 136.63, 132.51, 132.26, 130.69, 129.16, 128.62, 128.59, 127.71, 127.55, 126.93, 126.01, 125.49, 124.91, 124.27, 122.21, 120.43, 115.60, 112.87, 103.94, 61.65, 52.48, 21.25; Anal Calcd for C₂₈H₂₃Cl₂N₇O₄, C, 56.77, H, 3.91, N, 16.55; Found: C, 56.80, H, 3.95, N, 16.56.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)-2-methoxyphenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(3,5-dichlorophenyl)acetamide (11m)

White solid; isolated yield: 90%, mp: 247–249°C; IR (KBr, υ): 3282, 3056, 1668 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.88–11.69 (m, 2H), 10.87 (s, 1H), 8.48–8.39 (m, 1H), 8.33 (s, 1H), 7.75–7.68 (m, 1H), 7.67 (d, J = 1.9 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.42 (s, 1H), 7.39–7.34 (m, 1H), 7.33 (t, J = 1.9 Hz, 1H), 7.32–7.26 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 5.45 (s, 2H, N-CH₂), 5.27 (s, 2H, O-CH₂), 3.85 (s, 3H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 165.56, 158.06, 149.91, 149.78, 147.90, 142.78, 141.14, 137.30, 134.74, 130.67, 128.67, 127.98, 127.52, 127.03, 124.28, 123.56, 122.23, 120.43, 117.93, 113.50, 112.88, 108.95, 103.99, 62.05, 55.90, 52.74; Anal Calcd for C₂₈H₂₃Cl₂N₇O₄, C, 56.77, H, 3.91, N, 16.55; Found: C, 56.70, H, 3.94, N, 16.59.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)-2-methoxyphenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(4-bromophenyl)acetamide (11n)

White solid; isolated yield: 86%, mp: 172–174°C; IR (KBr, υ): 3289, 3056, 1665 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.97–11.60 (m, 2H), 10.70 (s, 1H), 8.53–8.38 (m, 1H), 8.32 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.64–7.51 (m, 6H), 7.43 (d, J = 4.5 Hz, 1H), 7.37 (s, 1H), 7.29–7.27 (m, 1H), 7.26–7.19 (m, 1H), 7.09 (t, J = 7.4 Hz, 1H), 5.42 (s, 2H, N-CH₂), 5.26 (s, 2H, O-CH₂), 3.84 (s, 3H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 164.90, 158.05, 149.78, 147.92, 138.26, 137.29, 130.66, 130.39, 127.98, 127.51, 127.20, 127.02, 126.32, 124.29, 122.22, 120.45, 120.42, 115.93, 110.17, 108.94, 104.02, 62.06, 55.90, 52.75; Anal Calcd for C₂₈H₂₄BrN₇O₄, C, 55.82, H, 4.02, N, 16.28; found: C, 55.80, H, 4.07, N, 16.23.

( E )-2-(4-((4-((2-(1 H -indole-2-carbonyl)hydrazono)methyl)-2-methoxyphenoxy)methyl)-1 H -1,2,3-triazol-1-yl)- N -(2-chloro-3-nitrophenyl)acetamide (11o)

White solid; isolated yield: 89%, mp > 250°C; IR (KBr, υ): 3282, 3056, 1663 cm^− 1; ¹H NMR (301 MHz, DMSO-d₆) δ 11.88–11.68 (m, 2H), 10.28 (s, 1H), 8.53–8.37 (m, 1H), 8.33 (s, 1H), 7.79–7.72 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.53–7.46 (m, 2H), 7.41 (s, 1H), 7.37–7.31 (m, 1H), 7.31–7.26 (m, 2H), 7.26–7.20 (m, 1H), 7.12–7.06 (m, 1H), 5.50 (s, 2H, N-CH₂), 5.26 (s, 2H, O-CH₂), 3.86 (s, 3H, O-CH₃); ¹³C NMR (76 MHz, DMSO-d₆) δ 165.51, 157.99, 151.40, 149.90, 149.77, 147.90, 142.81, 137.79, 137.27, 130.70, 130.29, 127.98, 127.50, 127.30, 127.03, 126.97, 125.98, 124.26, 122.20, 121.67, 120.42, 113.54, 112.87, 108.98, 103.94, 62.06, 56.52, 55.92; Anal Calcd for C₂₈H₂₃ClN₈O₆, C, 55.77, H, 3.84, N, 18.58; Found: C, 55.79, H, 3.80, N, 18.57.

In vitro α-glucosidase inhibition assay and kinetic study

In vitro α-glucosidase inhibition evaluations of the indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 11a-o and kinetic study of the most potent compounds 11d, 11n, and 11b were performed on yeast α‐glucosidase according to the literature [19].

Molecular modeling of the most potent compounds 11d and 11n in the active site of modeled α-glucosidase was carried out according to our previously described method [19]. Yeast form of α-glucosidase, Saccharomyces cerevisiae, that was used in in vitro assessments had not any crystallographic structure in the protein data bank, thus, our research team reconstructed a modeled enzyme using SWISS-MODEL Repository [21]. For this purpose, we used of a method that was described by Imran et al. [22, 23]. After searching by using SWISS-MODEL to find an appropriate enzyme with a high sequence similarity with Saccharomyces cerevisiae α-glucosidase in protein data bank, we selected Saccharomyces cerevisiae isomaltase with code of 3A4A in this bank. Saccharomyces cerevisiae isomaltase has 72% identical and 85% similarity with the Saccharomyces cerevisiae α-glucosidase. Next, Saccharomyces cerevisiae isomaltase was subjected through sequence alignment and homology model was reconstructed using by automated homology modeling pipeline SWISS-MODEL and the quality of the obtained constructed model was verified using PROCHECK [21].

The 3D structures of the most potent compounds 11d and 11n were built by MarvineSketch 5.8.3, 2012, ChemAxon (http://www.chemaxon.com) and converted to pdbqt coordinate using Auto dock Tools. The pdbqt coordinate of the target enzyme (modeled α-glucosidase) was created using Auto dock Tools. The obtained pdbqt file of the modeled α-glucosidase was used as an input file for the AUTOGRID program. In this program for each atom type in the title ligands, maps were calculated with 0.375 Å spacing between grid points and the center of the grid box was placed at x = 12.5825, y = -7.8955, and z = 12.519 Å. The appropriate dimensions for active site box were determined by BIOVIA Discovery Studio v.3.5 (40 × 40 × 40 Å). Flexible ligand dockings were accomplished for the title compounds. Each docked system for compounds 11n and 11d was carried out by 50 runs of the AUTODOCK search by the Lamarckian genetic algorithm. The best poses of the latter compounds were selected for analyzing the interactions between target enzyme and ligands. The results were visualized using BIOVIA Discovery Studio v.3.5 and the obtained data showed in Fig. 6 and Table 2.

In silico druglikeness/ADME/T studies

In silico druglikeness/ADME/T predictions of positive control acarbose and the most potent compounds 11d and 11n were performed using the preADMET online server [20].

In conclusion, we designed indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a-o as hybrid analogs of the active pharmacophores which previously have been reported as anti-α-glucosidase agents. Compounds 11a-o were synthesized in good yields. All of the synthesized compounds showed excellent inhibitory activity against α-glucosidase, more than positive control acarbose. Representatively, compound 11d with IC₅₀ value of 6.31 µM was 118.8 times more potent than acarbose. Kinetic studies of the most potent compounds 11d, 11n, and 11b revealed that these compounds are uncompetitive inhibitors against α-glucosidase. Molecular modeling of the most potent compounds 11d and 11n demonstrated that these compounds interact as well with important amino acids at active site. The latter compounds also have good pharmacokinetic properties as oral active compounds.

Declarations

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Not applicable.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors’ contributions

M.E. and M.M-K. performed the computational studies and wrote the manuscript. B.L. and A.A. supervised the practical experiments. F.M-M and S.H. synthesized and purified the compounds, and carried out ¹H NMR and ¹³C NMR. M.A. supervised the biological tests. S.M. performed the biological tests. Y.P and M.M. supervised the research. All authors reviewed the manuscript.

Acknowledgements

Not applicable.

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Supplementary Information

Author details

¹Electrical and Computer Engineering Department, Babol Noshirvani University of Technology, Babol, Iran. ²Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran. ³Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran ⁴Shahid Beheshti University of Medical Sciences, Tehran, Iran. ⁵Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. ⁶Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. ⁷Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.

No competing interests reported.

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Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: Design, synthesis, in vitro α-glucosidase inhibition, and computational studies

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