{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:59:54Z","timestamp":1787317194983,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T00:00:00Z","timestamp":1663200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004681","name":"Higher Education Commission of Pakistan","doi-asserted-by":"publisher","award":["NRPU-5614"],"award-info":[{"award-number":["NRPU-5614"]}],"id":[{"id":"10.13039\/501100004681","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The \u03b1-glucosidase enzyme, located in the brush border of the small intestine, is responsible for overall glycemic control in the body. It hydrolyses the 1,4-linkage in the carbohydrates to form blood-absorbable monosaccharides that ultimately increase the blood glucose level. \u03b1-Glucosidase inhibitors (AGIs) can reduce hydrolytic activity and help to control type 2 diabetes. Aiming to achieve this, a novel series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chloride was synthesized and screened for its \u03b1-glucosidase inhibitory potential. Compounds 5d, 5f, 5g, 5h and 5k exhibited better \u03b1-glucosidase inhibitions compared to the standard drug (acarbose IC50 = 58.8 \u00b1 0.012 \u00b5M) with IC50 values of 15 \u00b1 0.030, 19 \u00b1 0.060, 25 \u00b1 0.106, 21 \u00b1 0.07 and 26 \u00b1 0.035 \u00b5M, respectively. Furthermore, the molecular docking studies explored the mechanism of enzyme inhibitions by different 1,2,3-trisubstituted benzimidazolium salts via significant ligand\u2013receptor interactions.<\/jats:p>","DOI":"10.3390\/molecules27186012","type":"journal-article","created":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T01:35:10Z","timestamp":1663292110000},"page":"6012","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synthesis of Novel N-Methylmorpholine-Substituted Benzimidazolium Salts as Potential \u03b1-Glucosidase Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Imran Ahmad","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Chemistry, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Furqan Ahmad","family":"Saddique","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Aslam","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Government College Women University, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5495-805X","authenticated-orcid":false,"given":"Usman Ali","family":"Ashfaq","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biotechnology, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1302-8056","authenticated-orcid":false,"given":"Matloob","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami A.","family":"Al-Hussain","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdi E. A.","family":"Zaki","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dej-Adisai, S., Rais, I.R., Wattanapiromsakul, C., and Pitakbut, T. (2021). Alpha-glucosidase inhibitory assay-screened isolation and molecular docking model from Bauhinia Pulla active compounds. Molecules, 26.","DOI":"10.3390\/molecules26195970"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1016\/j.bmc.2009.01.061","article-title":"Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes","volume":"17","author":"Havale","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104168","DOI":"10.1016\/j.jff.2020.104168","article-title":"Hypoglycaemic effect of all-trans astaxanthin through inhibiting \u03b1-glucosidase","volume":"74","author":"Du","year":"2009","journal-title":"J. Funct. Foods"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"111738","DOI":"10.1016\/j.fct.2020.111738","article-title":"An overview on the role of bioactive \u03b1-glucosidase inhibitors in ameliorating diabetic complications","volume":"145","author":"Hossain","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"85","DOI":"10.4103\/0973-3930.53126","article-title":"Approaches in type 1 diabetes research: A status report","volume":"29","author":"Raha","year":"2009","journal-title":"Int. J. Diabetes Dev. Ctries"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jns.2019.10.304","article-title":"Correlation between risk factors for diabetic peripheral neuropathy and nerve conduction study parameters in children with type 1 diabetes mellitus attending Sudan childhood diabetes centre","volume":"405","author":"Musa","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1016\/j.clnu.2018.12.014","article-title":"Differentiating the effects of whey protein and guar gum preloads on postprandial glycemia in type 2 diabetes","volume":"38","author":"Watson","year":"2019","journal-title":"Clin Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1517\/13543784.2015.974804","article-title":"Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease","volume":"24","author":"Esser","year":"2015","journal-title":"Expert Opin. Inv. Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.pcd.2011.07.001","article-title":"Exploring reasons for very poor glycaemic control in patients with type 2 diabetes","volume":"5","author":"Khan","year":"2011","journal-title":"Prim Care Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"107826","DOI":"10.1016\/j.diabres.2019.107826","article-title":"Depression and risk of gestational diabetes: A meta-analysis of cohort studies","volume":"156","author":"Arafa","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jff.2018.07.022","article-title":"Exploring inhibitory mechanism of gallocatechin gallate on a-amylase and a-glucosidase relevant to postprandial hyperglycemia","volume":"48","author":"Wu","year":"2018","journal-title":"J. Funct. Foods"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103394","DOI":"10.1016\/j.bioorg.2019.103394","article-title":"Synthesis, in vitro alpha-glucosidase inhibitory potential of benzimidazole bearing bis-Schiff bases and their molecular docking study","volume":"94","author":"Rahim","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2174\/1389557517666171101104024","article-title":"Antimicrobial potential of benzimidazole derived molecules","volume":"19","author":"Bansal","year":"2019","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108178","DOI":"10.1016\/j.carres.2020.108178","article-title":"Synthesis of benzimidazole nucleosides and their anticancer activity","volume":"498","author":"Shinde","year":"2020","journal-title":"Carbohydr. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115403","DOI":"10.1016\/j.bmc.2020.115403","article-title":"Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15-lipoxygenase enzymes","volume":"28","author":"Maghraby","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113518","DOI":"10.1016\/j.ejmech.2021.113518","article-title":"Discovery and development of 2-aminobenzimidazoles as potent antimalarials","volume":"221","author":"Devine","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1016\/j.matpr.2020.07.347","article-title":"Antidiabetic (AD), stiffness and hardness studies of 2-[4-(Trifluoromethyl) phenyl]-1H-benzimidazole crystals-(TFMPHB) macro and nano crystal","volume":"33","author":"Flora","year":"2020","journal-title":"Mater. Today Proc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107400","DOI":"10.1016\/j.compbiolchem.2020.107400","article-title":"Alkylated benzimidazoles: Design, synthesis, docking, DFT analysis, ADMET property, molecular dynamics and activity against HIV and YFV","volume":"89","author":"Srivastava","year":"2020","journal-title":"Comput. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"130566","DOI":"10.1016\/j.molstruc.2021.130566","article-title":"Design, synthesis, antimicrobial evaluation, and molecular docking of novel chiral urea\/thiourea derivatives bearing indole, benzimidazole, and benzothiazole scaffolds","volume":"1241","author":"Lafzi","year":"2021","journal-title":"J. Mol. Struct."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.bioorg.2018.01.040","article-title":"Synthesis of benzimidazole-linked-1, 3, 4-oxadiazole carboxamides as GSK-3\u03b2 inhibitors with in vivo antidepressant activity","volume":"77","author":"Tantray","year":"2018","journal-title":"Bioorg. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Celik, I., Ayhan-Kilcigil, G., Guven, B., Kara, Z., and Onay-Besikci, A. (2021). In Vitro and in Silico Evaluation of Some New 1 H-Benzimidazoles Bearing Thiosemicarbazide and Triazole as Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. Polycycl. Aromat. Compd.","DOI":"10.1080\/10406638.2021.2015404"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105073","DOI":"10.1016\/j.bioorg.2021.105073","article-title":"A facile approach synthesis of benzoylaryl benzimidazole as potential \u03b1-amylase and \u03b1-glucosidase inhibitor with antioxidant activity","volume":"114","author":"Aroua","year":"2021","journal-title":"Bioorganic Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103482","DOI":"10.1016\/j.bioorg.2019.103482","article-title":"Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential \u03b1-glucosidase inhibitors","volume":"95","author":"Asemanipoor","year":"2020","journal-title":"Bioorganic Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.bioorg.2017.12.019","article-title":"A simple and efficient synthesis of benzimidazoles containing piperazine or morpholine skeleton at C-6 position as glucosidase inhibitors with antioxidant activity","volume":"76","author":"Parlak","year":"2018","journal-title":"Bioorganic Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1800029","DOI":"10.1002\/ardp.201800029","article-title":"meta-Cyanobenzyl substituted benzimidazolium salts: Synthesis, characterization, crystal structure and carbonic anhydrase, \u03b1-glycosidase, butyrylcholinesterase, and acetylcholinesterase inhibitory properties","volume":"351","author":"Turker","year":"2018","journal-title":"Arch. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"131504","DOI":"10.1016\/j.molstruc.2021.131504","article-title":"New benzimidazolium N-heterocyclic carbene precursors and their related Pd-NHC complex PEPPSI-type: Synthesis, structures, DFT calculations, biological activity, docking study, and catalytic application in the direct arylation","volume":"1248","author":"Sandeli","year":"2022","journal-title":"J. Mol. Struct."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.bmc.2016.02.012","article-title":"Functionalized imidazolium and benzimidazolium salts as paraoxonase 1 inhibitors: Synthesis, characterization and molecular docking studies","volume":"24","author":"Karatas","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"855","DOI":"10.3390\/chemistry4030061","article-title":"A Benzimidazolium-Based Organic Cage with Antimicrobial Activity","volume":"4","author":"Armentano","year":"2022","journal-title":"Chemistry"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Khan, I.A., Ahmad, M., Ashfaq, U.A., Sultan, S., and Zaki, M.E. (2021). Discovery of Amide-Functionalized Benzimidazolium Salts as Potent \u03b1-Glucosidase Inhibitors. Molecules, 26.","DOI":"10.3390\/molecules26164760"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.2174\/09298673113209990001","article-title":"Virtual screening strategies in drug discovery: A critical review","volume":"20","author":"Lavecchia","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_31","first-page":"1","article-title":"Molecular docking as a popular tool in drug design, an in silico travel","volume":"6","author":"Ruyck","year":"2016","journal-title":"Adv. Appl. Bioinform. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/157340911795677602","article-title":"Molecular docking: A powerful approach for structure-based drug discovery. Curr. Comput","volume":"7","author":"Meng","year":"2011","journal-title":"Aided Drug Des."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s10822-012-9551-4","article-title":"Pose prediction and virtual screening performance of GOLD scoring functions in a standardized test","volume":"26","author":"Liebeschuetz","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4420","DOI":"10.1016\/j.bmcl.2010.06.059","article-title":"Docking and SAR studies of salacinol derivatives as \u03b1-glucosidase inhibitors","volume":"20","author":"Nakamura","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.3746\/pnf.2020.25.3.263","article-title":"Investigation of anthocyanidins and anthocyanins for targeting \u03b1-glucosidase in diabetes mellitus","volume":"25","author":"Promyos","year":"2020","journal-title":"Prev. Nutr. Food Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.24198\/ijpst.v7i1.23062","article-title":"In Silico study of aglycon curculigoside A and its derivatives as \u03b1-amylase inhibitors","volume":"7","author":"Nursamsiar","year":"2020","journal-title":"Indones. J. Pharm. Sci. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Saddique, F.A., Aslam, S., Ahmad, M., Ashfaq, U.A., Muddassar, M., Sultan, S., Taj, S., Hussain, M., Lee, D.S., and Zaki, M.E.A. (2021). Synthesis and \u03b1-Glucosidase Inhibition Activity of 2-[3-(Benzoyl\/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo [e][1,2]thiazin-2-yl]-N-arylacetamides: An In silico and Biochemical Approach. Molecules, 26.","DOI":"10.3390\/molecules26103043"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Saddique, F.A., Ahmad, M., Ashfaq, U.A., Muddassar, M., Sultan, S., and Zaki, M.E.A. (2022). Identification of Cyclic Sulfonamides with an N-Arylacetamide Group as \u03b1-Glucosidase and \u03b1-Amylase Inhibitors: Biological Evaluation and Molecular Modeling. Pharmaceuticals, 15.","DOI":"10.3390\/ph15010106"},{"key":"ref_39","first-page":"1739","article-title":"Molecular Docking Study on Xanthone Derivatives toward Alpha-Glucosidase","volume":"7","author":"Lakehal","year":"2016","journal-title":"Res. J. Pharm. Biol. Chem. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"42","DOI":"10.7324\/JAPS.2015.501207","article-title":"In silico investigation of black tea components on \u03b1 -amylase, \u03b1 -glucosidase and lipase","volume":"5","author":"Mohapatra","year":"2015","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sochacka-Cwikla, A., Maczynski, M., and Regiec, A. (2022). FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021. Molecules, 27.","DOI":"10.3390\/molecules27072259"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"104002","DOI":"10.1016\/j.bioorg.2020.104002","article-title":"Synthesis, \u03b1-Glucosidase Inhibition and in Silico Studies of Some 4-(5-Fluoro-2-substituted- 1H-benzimidazol-6-yl) morpholine Derivatives","volume":"101","author":"Mentese","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-08-096807-0.00001-4","article-title":"Heterocycles and medicine: A survey of the heterocyclic drugs approved by the US FDA from 2000 to present","volume":"Volume 24","author":"Wu","year":"2012","journal-title":"Progress in Heterocyclic Chemistry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.bioorg.2016.04.006","article-title":"Synthesis, molecular docking and \u03b1-glucosidase inhibition of 5-aryl-2-(6\u2032-nitrobenzofuran-2\u2032-yl)-1, 3, 4-oxadiazoles","volume":"66","author":"Taha","year":"2016","journal-title":"Bioorg. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bioorg.2015.11.006","article-title":"Benzimidazole derivatives as new \u03b1-glucosidase inhibitors and in silico studies","volume":"64","author":"Zawawi","year":"2016","journal-title":"Bioorg. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.lfs.2012.11.022","article-title":"Studies on \u03b1-glucosidase inhibition and anti-glycation potential of Iris loczyi and Iris unguicularis","volume":"92","author":"Mosihuzzman","year":"2013","journal-title":"Life Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/6012\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:32:09Z","timestamp":1760142729000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/6012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,15]]},"references-count":46,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["molecules27186012"],"URL":"https:\/\/doi.org\/10.3390\/molecules27186012","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,15]]}}}