Synthesis, Glucosidase Inhibition, and In Silico Modeling Analysis of Highly Fluorinated 2-Imino-1,3-thiazolines in Search of Potent Antidiabetic Agents

Lutf Ullah Zahid; Sumera Zaib; Aamer Saeed; Hussam Y Alharbi; Majed S Aljohani; Osama Alharbi; Nehal Rana; Imtiaz Khan; Ghulam Shabir; Atteeque Ahmed; Arslan Saleem; Nasser S Awwad; Hala A Ibrahium

doi:10.1021/acsomega.4c00529

Synthesis, Glucosidase Inhibition, and In Silico Modeling Analysis of Highly Fluorinated 2-Imino-1,3-thiazolines in Search of Potent Antidiabetic Agents

ACS Omega. 2024 Mar 20;9(13):15603-15614. doi: 10.1021/acsomega.4c00529. eCollection 2024 Apr 2.

Authors

Affiliations

¹ Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
² Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan.
³ Department of Chemistry, Faculty of Science, Taibah University, Yanbu 46423, Saudi Arabia.
⁴ Department of Chemistry, Faculty of Science, Taibah University, Madinah 42353, Saudi Arabia.
⁵ Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, U.K.
⁶ Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia.
⁷ Biology Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia.

Abstract

In the present work, 2-imino-1,3-thiazolines featuring highly fluorinated fragments were synthesized through a straightforward cyclization of diversely substituted thioureas with 2-bromo-1-(4-fluorophenyl)ethan-1-one. The target compounds were obtained in good yields, and structures were established by FTIR and ¹H- and ¹³C NMR spectroscopic methods. The in vitro biological assay revealed that all the compounds significantly obstruct the α-glucosidase. Compound 6d (3-fluoro-N-(3-(2-fluorophenyl)-4-(4-fluorophenyl)thiazol-2(3H)-ylidene)benzamide) showed the highest antidiabetic potential with an IC₅₀ value of 1.47 ± 0.05 μM. In addition, computational analysis revealed the binding energy of -11.1 kcal/mol for 6d which was lower than the positive standard, acarbose (-7.9 kcal/mol). Several intermolecular interactions between the active site residues and 6d highlight the significance of 2-imino-1,3-thiazoline core in attaining the potent efficacy and making these compounds a valuable pharmacophore in drug discovery.