Original Article DESIGN AND IN SILICO EVALUATION OF PHENOXY ACETAMIDE DERIVATIVES AS POTENTIAL ANTIDIABETIC AGENTS INDHUMATHI S. 1 , S. SREE NITHI 1 , GOBIANANTH 1 , MOHD ABDUL BAQI 2* , N. VENKATHESHAN 1 , GANESH MEENA 2 , KOPPULA JAYANTHI 1* 1 Department of Pharmaceutical Chemistry, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India. 2 Department of Pharmaceutics, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India. 3 Department of Pharmaceutical Chemistry, Chemistry, Arulumigu Kalasalingam College of Pharmacy, Kalasalingam Academy of Research and Education, Krishnan Koil, Tamil Nadu, India * Corresponding author: Koppula Jayanthi; * Email: jayanthi.k@akcp.ac.in Received: 06 May 2025, Revised and Accepted: 04 Jul 2025 ABSTRACT Objective: This study explores the interactions of phenoxy acetamide derivatives with AMP-activated protein kinase (AMPK), a key enzyme in metabolic regulation. The goal is to evaluate the AMPK activation potential of these compounds using in silico approaches. Methods: Molecular docking was performed using the Glide module to assess binding affinity. Binding free energy (ΔG_bind) was calculated using the MM-GBSA method, and pharmacokinetic profiles were evaluated via ADME predictions using QikProp. Results: Among the tested compounds, 3-chlorophenyl phenoxy acetamide (compound 5) exhibited the highest XP-docking score of –5.22 kcal/mol and a ΔG_bind of –97.78 kcal/mol, indicating strong binding with the AMPK active site. Key interactions included hydrogen bonding with residues PRO127, MET84, ARG117, and TYR120. ADME analysis revealed that all compounds showed low CNS penetration (QPlog BB<–1) and acceptable intestinal absorption (Caco-2>300 nm/s). Conclusion: Compound 5 demonstrates significant AMPK activation potential and favorable ADME properties, suggesting its promise as a lead compound for type II diabetes therapy. Keywords: Molecular docking, MM-GBSA, Phenoxy-acetamide, AMPK, ADME, Type II diabetes © 2025 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2025v17i5.54892 Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. It poses a significant global health challenge, affecting over 537 million adults as of 2021, with projections estimating an increase to 643 million by 2030 and 783 million by 2045 [1]. Among its types, type 2 diabetes mellitus T2DM accounts for more than 90% of all diabetes cases and is predominantly associated with insulin resistance and relative insulin deficiency [2]. The pathophysiology of T2DM involves a complex interplay of impaired insulin signaling, reduced glucose uptake by peripheral tissues such as skeletal muscle and adipose tissue, hepatic overproduction of glucose, and chronic inflammation [3]. If left untreated, T2DM can lead to serious complications, including cardiovascular disease, nephropathy, neuropathy, retinopathy, and increased mortality. Globally, diabetes was responsible for approximately 6.7 million deaths in 2021, underscoring the urgent need for effective and sustainable therapeutic strategies. Management of T2DM typically involves lifestyle interventions and pharmacological therapy. Insulin, discovered in the early 1920s, was the first antidiabetic drug and remains essential, particularly for type 1 diabetes. The introduction of oral antidiabetic agents, notably sulfonylureas and biguanides such as metformin, expanded treatment options significantly. Metformin continues to be the first-line treatment due to its efficacy, safety profile, and affordability [4]. In recent years, new drug classes have emerged, targeting diverse mechanisms of glucose regulation. These include thiazolidinediones, which enhance insulin sensitivity; DPP-4 inhibitors, which prolong incretin hormone activity; SGLT2 inhibitors, which reduce renal glucose reabsorption; and GLP-1 receptor agonists, which enhance insulin secretion and promote weight loss. Despite these advancements, the therapeutic landscape is still challenged by issues such as drug resistance, adverse effects, and the inability to fully prevent disease progression in many patients. Given the multifactorial nature of T2DM, there remains a pressing need to develop new therapeutic agents that are safer, more effective, and capable of targeting multiple pathways involved in disease progression. In this context, in silico approaches have become an essential tool in modern drug discovery, enabling researchers to identify and optimize lead compounds rapidly and cost-effectively [5]. These computational techniques facilitate virtual screening and prediction of molecular interactions with key antidiabetic targets, streamlining early-phase drug development. Phenoxy acetamide derivatives have recently gained attention due to their structural versatility and broad biological activities, including antioxidant, anti-inflammatory, and antidiabetic potential [6]. Their chemical framework allows for functional modifications that may enhance binding affinity and selectivity toward metabolic targets. One particularly promising target in the treatment of T2DM is AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. Activation of AMPK enhances glucose uptake, fatty acid oxidation, and insulin sensitivity while suppressing hepatic gluconeogenesis. Recent evidence also suggests that AMPK activation can stimulate pancreatic β-cell function and promote insulin secretion, providing a dual therapeutic benefit. Therefore, the identification of small molecules capable of activating AMPK offers a strategic approach to improving glycemic control and preserving β-cell function in diabetic patients. The present study aims to design and evaluate novel phenoxy acetamide derivatives using in silico methodologies to identify promising candidates for antidiabetic therapy. Special emphasis is placed on the interaction of these compounds with AMPK, with the goal of identifying activators that can enhance insulin production and improve metabolic regulation. Molecular docking studies will be employed to investigate their binding affinity and potential efficacy. The findings of this research are expected to contribute to the development of more effective therapeutic agents for managing type 2 diabetes mellitus. MATERIALS AND METHODS Protein preparation The protein structure was prepared using the Protein Preparation Wizard at physiological pH (7.0). Key catalytic residues, such as lysine, were assigned standard protonation states appropriate for International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 17, Issue 5, 2025