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. 2022 Nov 21:16:4021-4039.
doi: 10.2147/DDDT.S357604. eCollection 2022.

Design of 1,4-Dihydropyridine Hybrid Benzamide Derivatives: Synthesis and Evaluation of Analgesic Activity and Their Molecular Docking Studies

Idhayadhulla Akbar  1 , Surendrakumar Radhakrishnan  1 , Karpakavalli Meenakshisundaram  2 , Aseer Manilal  3 , Ashraf Atef Hatamleh  4 , Bassam Khalid Alnafisi  4 , Anis Ahamed  4 , Ravindran Balasubramani  5
Affiliations

Design of 1,4-Dihydropyridine Hybrid Benzamide Derivatives: Synthesis and Evaluation of Analgesic Activity and Their Molecular Docking Studies

Idhayadhulla Akbar et al. Drug Des Devel Ther. .

Abstract

Purpose: This study aims to determine the analgesic activity of 1,4-dihydropyridine hybrid benzamide derivatives. These hybrid derivatives were synthesized, and their analgesic activity was studied. The synthesis method applied was a one-step reaction involving a green chemistry approach.

Methods: The compounds were prepared via the amination method with a yield ranging between 82% and 93%. The title compounds were confirmed by means of IR, 1H and 13C NMR, and mass spectral analyses. The pharmacological activity of all the synthesized compounds was evaluated, and the analgesic activities were monitored in vivo (by tail immersion methods), with a digital analgesiometer. The drug response and damage of tail ata concentration of 10 mg/kg were measured by tail-flicking latency.

Results: The activity of compound 2c (81.35% activity at 5mg/kg) can be correlated with its salicylamidemoiety (13.99% activity at 5mg/kg), and diclofenac showed comparable activity (79.21% activity at 5mg/kg reference drugs). Compound 2c has a higher potential to inhibit COX proteins compared to diclofenac. The drug-like nature of the molecule 2c corresponds to its ADME properties.

Conclusion: In this study, all the synthesized compounds were found to possess significant analgesic activities; particularly, the performance of compound 2c is excellent. Thus, the preparative method described is an apt route for developing novel therapeutic formulations.

Keywords: 1,4-dihydropyridine; amination method; analgesic activity; diclofenac; molecular docking; salicylamide.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Pharmaceutically active compounds 1,4-dihydroyridine and other amide derivatives.
Scheme 1
Scheme 1
Method for synthesizing compounds (2a-g, 3a-g).
Figure 2
Figure 2
Analgesic activities of compounds 2a-g, and 3a-g at 10mg/kg (60min).
Figure 3
Figure 3
Structure–activity relationship of compounds 2c and 3c.
Figure 4
Figure 4
The binding of 2c with 1CX2 protein complex: (A) Docking complex; (B) Molecular surface; (C) 3D interaction; (D) 2D interaction.
Figure 5
Figure 5
The binding of diclofenac with 1CX2 protein complex: (A) Docking complex; (B) Molecular surface; (C) 3D interaction; (D) 2D interaction.
Figure 6
Figure 6
The binding of 2c with2OYE protein complex: (A) Docking complex; (B) Molecular surface; (C) 3D interaction; (D) 2D interaction.
Figure 7
Figure 7
The binding of diclofenac with 2OYE protein: (A) Docking complex; (B) Molecular surface; (C) 3D interaction; (D) 2D interaction.
See this image and copyright information in PMC

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