{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T16:27:22Z","timestamp":1792945642463,"version":"4.5.0"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023674","name":"Deanship of Scientific Research, King Khalid University","doi-asserted-by":"publisher","award":["RGP2\/84\/46"],"award-info":[{"award-number":["RGP2\/84\/46"]}],"id":[{"id":"10.13039\/501100023674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Compounds containing an azomethine functional group are well recognized for their enzyme inhibitory potential. In this study, a series of hydrazone-Schiff base derivatives from 4-(tert-butyl)benzoic acid was synthesized and evaluated for their inhibitory activity against \u03b1-amylase, \u03b1-glucosidase, and tyrosinase. assays demonstrated pronounced multi-target inhibition. Against \u03b1-amylase, compound\n                    <jats:bold>2l<\/jats:bold>\n                    , bearing a para-nitro substituent, exhibited strong activity with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 2.72\u2009\u00b1\u20090.09 \u00b5M, significantly outperforming the reference acarbose (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200916.06\u2009\u00b1\u20090.05 \u00b5M; p\u2009&lt;\u20090.001). Similarly, compound\n                    <jats:bold>2l<\/jats:bold>\n                    showed potent \u03b1-glucosidase inhibition (IC\n                    <jats:sub>50<\/jats:sub>\n                    of 3.96\u2009\u00b1\u20090.21 \u00b5M), which was markedly superior to acarbose (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200916.65\u2009\u00b1\u20090.07 \u00b5M; p\u2009&lt;\u20090.001). In the tyrosinase inhibition assay, the dimethoxy-substituted derivative\n                    <jats:bold>2r<\/jats:bold>\n                    emerged as the most active compound, with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 5.61\u2009\u00b1\u20090.03 \u00b5M, approximately threefold more potent than kojic acid (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200915.29\u2009\u00b1\u20091.04 \u00b5M; p\u2009&lt;\u20090.001). Molecular docking studies against \u03b1-amylase, \u03b1-glucosidase, and tyrosinase (PDB IDs: 3BAJ, 5NN5, and 5M8Q, respectively) revealed favorable binding energies ranging from \u22125.2 to \u22125.8 kcal\/mol and highlighted key interactions with catalytic residues. Density functional theory (DFT) and molecular electrostatic potential (MEP) analyses provided an electronic basis for the observed structure-activity relationships, indicating that enhanced electrophilicity favors glycosidase inhibition, whereas increased nucleophilicity contributes to tyrosinase inhibition. Overall, these findings identify hydrazone Schiff base derivatives as promising scaffolds for the development of multifunctional enzyme inhibitors, with compounds\n                    <jats:bold>2l<\/jats:bold>\n                    and\n                    <jats:bold>2r<\/jats:bold>\n                    representing potential lead candidates for further optimization.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0348140","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T17:51:52Z","timestamp":1778521912000},"page":"e0348140","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hydrazone-schiff base derivatives of 4-(tert-butyl)benzoic acid as potent enzyme inhibitors: In vitro \u03b1-amylase, \u03b1-glucosidase, tyrosinase inhibition and computational studies"],"prefix":"10.1371","volume":"21","author":[{"given":"Imen","family":"Zghab","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajjad","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imtiaz","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-2376","authenticated-orcid":true,"given":"Aftab","family":"Alam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shah","family":"Mulk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masroor","family":"Kamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferjeni","family":"Zouidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9379-2155","authenticated-orcid":true,"given":"Abdulrahman S.","family":"Alharbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Elhenawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momin","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"issue":"1","key":"pone.0348140.ref001","doi-asserted-by":"crossref","first-page":"1040693","DOI":"10.1155\/2022\/1040693","article-title":"Molecular docking, synthesis, and tyrosinase inhibition activity of acetophenone amide: potential inhibitor of melanogenesis","volume":"2022","author":"Y Nazir","year":"2022","journal-title":"BioMed Research International"},{"issue":"11","key":"pone.0348140.ref002","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1002\/pi.5194","article-title":"Melanin from a physicochemical point of view","volume":"65","author":"JM Menter","year":"2016","journal-title":"Polymer International"},{"issue":"11","key":"pone.0348140.ref003","doi-asserted-by":"crossref","first-page":"5862","DOI":"10.3390\/ijms25115862","article-title":"Melanin for Photoprotection and Hair Coloration in the Emerging Era of Nanocosmetics","volume":"25","author":"A Menichetti","year":"2024","journal-title":"Int J Mol Sci"},{"key":"pone.0348140.ref004","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3389\/fendo.2013.00049","article-title":"The role of melanin-concentrating hormone and its receptors in energy homeostasis","volume":"4","author":"DJ Macneil","year":"2013","journal-title":"Front Endocrinol (Lausanne)"},{"key":"pone.0348140.ref005","doi-asserted-by":"crossref","unstructured":"Wang Y, Jiang R, Xiong B, Zhu J, Sang J, Li H, et al. 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