Drug Design, Development and Therapy (Nov 2022)
Design, Synthesis and Pharmacological Evaluation of 2-(3-BenzoyI-4-Hydroxy-1,1-Dioxido-2H-Benzo[e][1,2]thiazin-2-yI)-N-(2-Bromophenyl) Acetamide as Antidiabetic Agent
Abstract
Fatima Rashid,1 Matloob Ahmad,2 Usman Ali Ashfaq,1 Aamal A Al-Mutairi,3 Sami A Al-Hussain3 1Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan; 2Department of Chemistry, Government College University, Faisalabad, Pakistan; 3Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi ArabiaCorrespondence: Usman Ali Ashfaq, Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan, Email [email protected] Sami A Al-Hussain, Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia, Email [email protected]: The present study is based on screening new and potent synthetic heterocyclic compounds as anti-diabetic drugs using various computational tools, lab experiments, and animal models.Methods: A potent synthetic compound 2-(3-benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-1-(2-bromophenyl) acetamide (FA2) was checked against diabetes and screened via enzyme inhibition assays, enzyme kinetics against alpha-glucosidase and alpha-amylase. Protein–ligand interaction was analyzed via molecular docking and toxicological analysis via ADMET. Experimental animals were used to examine the compound FA2 safety, delivery, and check various biochemical tests related to diabetes like fasting glucose sugar, cholesterol, triglyceride, HbAc1, creatinine, and insulin level. Histography of liver, kidney, and pancreas was also performed.Results: Results showed that FA2 had binding energy of ‐7.02 Kcal/mol and ‐6.6 kcal/mol against α‐glucosidase (PDB ID: 2ZE0) and α‐amylase (PDB ID: 1B2Y), respectively. Moreover, in vitro enzyme inhibition assays and enzyme kinetics against α‐glucosidase and α‐amylase were performed, and FA2 showed IC50 at 5.17 ± 0.28 μM and 18.82 ± 0.89 μM concentrations against α‐glucosidase and α‐amylase, respectively. Kinetics studies showed that the FA2 compound impeded α‐glucosidase and α-amylase as a non-competitive mode of inhibition with Ki’ values − 0.320 ± 0.001 and 0.141 ± 0.01, respectively. FA2 was further analyzed on alloxan-induced mice for 21 days. Biochemical tests (fasting glucose sugar, cholesterol, triglyceride, HbAc1, creatinine, and insulin levels) and histological examination of liver and kidney showed that the FA2 compound showed better results than acarbose. Histology of pancreas found to show the maintenance of normal pancreatic acini and Langerhans islets in FA2 treated mice compared to acarbose and nontreated diabetic controls.Conclusion: Investigating anti-diabetic potential of FA2 compound showed that the selected benzothiazine derivative has tremendous importance in reducing dose concentration and side effects.Graphical Abstract: Keywords: diabetes, benzothiazine, enzyme kinetics, mice model, drug discovery
