Innovation of 6-sulfonamide-2 H-chromene derivatives as antidiabetic agents targeting α-amylase, α-glycosidase, and PPAR-γ inhibitors with in silico molecular docking simulation

Abstract

A new series of 2-imino or 2-oxo-2H-chromene-6-sulfonamide derivatives 2-9 with potential anti-diabetic activity were designed and synthesized. The new 6-sulfonamide chromenes were synthesized by reacting 3-formyl-4-hydroxybenzenesulfonyl chloride with activated methylene derivatives in the presence of ammonium acetate as a catalyst. The structure of the products was confirmed by spectroscopic analysis. All the designed derivatives 2-9 were evaluated for their activity against α-amylase and exhibited inhibitory percentage values higher than 93% at 100 μg mL^-1. Additionally, the IC₅₀ values represented a variable degree of activity with two derivatives 2 and 9 exhibiting the most promising derivative results with IC₅₀ values of 1.76 ± 0.01 and 1.08 ± 0.02 μM, respectively, compared to Acarbose (IC₅₀ = 0.43 ± 0.01 μM). Additionally, these derivatives showed potency against the α-glucosidase enzyme with IC₅₀ values of 0.548 ± 0.02 and 2.44 ± 0.09 μg mL^-1, compared to Acarbose (0.604 ± 0.02 μg mL^-1). Moreover, the in vitro PPAR-γ transactivation assay revealed that chromene-6-sulfonamide derivatives 2 and 9 exhibited potential PPAR-γ activity with IC₅₀ values of 3.152 ± 0.03 and 3.706 ± 0.32 μg mL^-1, respectively, compared to Pioglitazone (4.884 ± 0.29 μg mL^-1). This indicates that these derivatives have insulin sensitivity and glucose metabolism activity. The in silico ADMET prediction showed that these derivatives have an acceptable range of oral bioavailability, drug-likeness, and a safe toxicity profile, including being non-cytotoxic, non-mutagenic, non-immunotoxic, and non-carcinogenic. Finally, computational docking analysis demonstrated the ability of these derivatives to interact with α-amylase, α-glucosidase, and PPAR-γ enzymes, with confirmed successful placement due to good binding energy values and various interactions within the pocket.

Fig. 1. Structure of the previously reported chromone derivatives as anti-diabetic agents as α-glucosidase and α-amylase inhibitors.

Scheme 1. Illustrate synthesis of 3-substituted-2-imino-2H-chromene-6-sulfonamide 2 & 3 and 3-substituted-2-oxo-2H-chromene-6-sulfonamide 4 & 5.

Scheme 2. Mechanism illustrated the synthetic approach of 3-cyano-2-imino-2H-chromene-6-sulfonamide 2.

Scheme 3. Synthesis of the target N-(substitutedphenyl)-2-imino-6-sulfamoyl-2H-chromene-3-carboxamide 6–9.

Fig. 2. General structure with different substituents that exhibited the activity and SAR study of the newly designed chromene derivatives 2–9.

Fig. 3. 3D interaction of (A) co-crystallized Acarbose as superimposable (green is the original pose, while turquoise is our pose), (B) compound 2, and (C) compound 9 inside the active site of α-amylase (PDB: 2QV4).

Fig. 4. 3D interaction of (A) co-crystallized Acarbose as superimposable (green is the original pose, while turquoise is our pose), (B) compound 2, and (C) compound 9 inside the active site of α-glucosidase (PDB: 3w37).

Fig. 5. 3D interaction of (A) co-crystallized Ligand as superimposable (green is the original pose, while turquoise is our pose), (B) compound 2, and (C) compound 9, and (D) Pioglitazone inside the active site of PPAR-γ (PDB: 3SZ1).