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In this study, a series of previously reported aryl-substituted unnatural\n                    <jats:italic>N<\/jats:italic>\n                    -methoxysulfonyl \u03b2-ketoester derivatives were investigated for their inhibitory potential against ALR2, \u03b1-glucosidase, and \u03b1-amylase. Compound\n                    <jats:bold>1i<\/jats:bold>\n                    exhibited the strongest ALR2 inhibition with K\n                    <jats:sub>i<\/jats:sub>\n                    :0.493\u2009\u00b1\u20090.155 \u00b5M and IC\n                    <jats:sub>50<\/jats:sub>\n                    : 1.638\u2009\u00b1\u20090.44\u00a0\u00b5M. For \u03b1-glucosidase, compound\n                    <jats:bold>1h<\/jats:bold>\n                    showed the highest potency (K\n                    <jats:sub>i<\/jats:sub>\n                    :1.341\u2009\u00b1\u20090.181\u00a0\u00b5M), while compound\n                    <jats:bold>1j<\/jats:bold>\n                    demonstrated strong \u03b1-amylase inhibition (IC\n                    <jats:sub>50<\/jats:sub>\n                    : 1.361\u2009\u00b1\u20090.26\u00a0\u00b5M). The compounds were evaluated through in vitro enzyme inhibition assays supported by comprehensive structure\u2013activity relationship (SAR) analysis. Several derivatives displayed pronounced inhibitory activity, achieving sub-micromolar K\n                    <jats:sub>i<\/jats:sub>\n                    values against ALR2 and low-micromolar inhibition of \u03b1-glucosidase and \u03b1-amylase, in some cases surpassing reference inhibitors. SAR analysis revealed that ALR2 inhibition is strongly governed by planar aromatic expansion and conformational rigidity, whereas \u03b1-glucosidase and \u03b1-amylase preferentially accommodate compact, hydrophobically enriched substituents, highlighting distinct steric and electronic requirements across targets. A strong correlation was observed between experimental and docking-derived K\n                    <jats:sub>i<\/jats:sub>\n                    values, supporting the consistency of the computational protocol. Subsequent 100\u00a0ns molecular dynamics simulations confirmed the stability of the most active ligand\u2013enzyme complexes under physiological conditions. Overall, this integrated experimental and computational evaluation identifies unnatural\n                    <jats:italic>N<\/jats:italic>\n                    -methoxysulfonyl \u03b2-ketoester derivatives as promising multitarget antidiabetic lead scaffolds.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05249-1","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T11:57:53Z","timestamp":1774439873000},"page":"13385-13404","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unnatural amino acid compounds as potent multi-target inhibitors of aldose reductase, \u03b1-glucosidase, and \u03b1-amylase: integrated in vitro, SAR, and molecular dynamics insights"],"prefix":"10.1007","volume":"399","author":[{"given":"Serpil","family":"Gerni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cansu","family":"\u00d6zt\u00fcrk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song\u00fcl","family":"Bayrak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeliz","family":"Demir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ufuk","family":"Atmaca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejan","family":"Milenkovi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Du\u0161an","family":"Dimi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6mer \u0130rfan","family":"K\u00fcfrevio\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"5249_CR1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","volume":"1","author":"MJ Abraham","year":"2015","unstructured":"Abraham MJ, Murtola T, Schulz R, P\u00e1ll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. 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