Anti-Diabetic Activities and Molecular Docking Studies of Aryl-Substituted Pyrazolo[3,4-b]pyridine Derivatives Synthesized Via Suzuki Cross-Coupling Reaction

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2024 Oct 26

PMID 39458967

Authors

Iqra Rafique

Tahir Maqbool

Floris P J T Rutjes

Ali Irfan

Yousef A Bin Jardan

Affiliations

Soon will be listed here.

Abstract

Pyrazolo[3,4-]pyridine scaffolds have been heavily exploited in the development of nitrogen-containing heterocycles with numerous therapeutic applications in the field of medicinal and pharmaceutical chemistry. The present work describes the synthesis of eighteen biaryl pyrazolo[3,4-]pyridine ester (-) and hydrazide (-) derivatives via the Suzuki cross-coupling reaction. These derivatives were subsequently screened for their therapeutic potential to inhibit the diabetic α-amylase enzyme, which is a key facet of the development of anti-diabetic agents. Initially, the ethyl 4-(4-bromophenyl)-3-methyl-1-phenyl-1-pyrazolo[3,4-]pyridine-6-carboxylate was synthesized through a modified Doebner method under solvent-free conditions, providing an intermediate for further derivatization with a 60% yield. This intermediate was subjected to Suzuki cross-coupling, reacting with electronically diverse aryl boronic acids to obtain the corresponding pyrazolo[3,4-]pyridine ester derivatives (-). Following this, the biaryl ester derivatives (-) were converted into hydrazide derivatives (-) through a straightforward reaction with hydrazine monohydrate and were characterized using H-NMR, C-NMR, and LC-MS spectroscopic techniques. These derivatives were screened for their α-amylase inhibitory chemotherapeutic efficacy, and most of the biaryl ester and hydrazide derivatives demonstrated promising amylase inhibition. In the (-) series, the compounds , , , and exhibited excellent inhibition, with almost similar IC values of 5.14, 5.15, 5.56, and 5.20 μM, respectively. Similarly, in the series (-), the derivatives , , , , , , and displayed excellent anti-diabetic activities of 5.21, 5.18, 5.17, 5.12, 5.10, 5.16, and 5.19 μM, respectively. These in vitro results were compared with the reference drug acarbose (IC = 200.1 ± 0.15 μM), demonstrating better anti-diabetic inhibitory activity in comparison to the reference drug. The in silico molecular docking study results were consistent with the experimental biological findings, thereby supporting the in vitro pharmaceutical efficacy of the synthesized derivatives.

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