{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:12:58Z","timestamp":1788437578547,"version":"build-2803163510"},"reference-count":42,"publisher":"American Chemical Society (ACS)","issue":"34","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007288","name":"Mahasarakham University","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100007288","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014795","name":"Center of Excellence for Innovation in Chemistry","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100014795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The roots of Croton krabas have traditionally been used as a water decoction for treatment of bloating and flatulence. The preliminary bioactivity screening revealed that the crude n-hexane and EtOAc extracts exhibited significant \u03b1-glucosidase inhibitory activity. Accordingly, the first phytochemical investigation of the roots of C. krabas led to the isolation of two previously undescribed clerodane diterpenes (1 and 2), together with eight known compounds (3\u201310). The structures and stereochemistry were elucidated by extensive analysis of spectroscopic data (UV, IR, 1H NMR, 13C NMR, and 2D NMR), mass spectrometry (MS), ECD calculation, and comparison with reported data. The structure of 2, a rare hybrid diterpene ester comprising both clerodane and ent-kaurane units, was further confirmed by alcoholysis and ESI-MS\/MS fragmentation analyses. Among these, 12-oxo-hardwickiic acid (7) was obtained as a major clerodane and exhibited potent \u03b1-glucosidase inhibitory activity. To enhance its activity, 7 was structurally modified through esterification and reaction with hydrazine hydrate, guided by molecular docking simulations, yielding two esters 2a and 7a and three pyridazines 7b\u20137d derivatives. A plausible reaction mechanism for the formation of the pyridazine derivatives is also proposed. Isolated clerodanes 2, 6, and 7 exhibited potent \u03b1-glucosidase inhibition, surpassing the standard drug acarbose (IC50 = 341.10 \u03bcM). Moreover, the clerodane ester derivatives 2a and 7a showed strong inhibitory activity with IC50 values of 27.23 and 14.29 \u03bcM, respectively, which were more potent than both parent clerodane and acarbose. In contrast, the pyridazine derivatives 7b\u20137d (IC50 = 272.40\u2013290.63 \u03bcM) reduced activity compared to their parent clerodane, although they remained more active than acarbose. Molecular docking studies revealed that 6, 7, 2a, and 7a\u20137d blocked substrate from the entrance of \u03b1-glucosidase active site. Furthermore, the predicted physicochemical properties of these compounds complied with Lipinski\u2019s and Veber\u2019s rules, while ADMET analyses indicated favorable pharmacokinetic profiles. These findings suggest that the clerodane ester derivatives 2a and 7a represent promising candidates for the development of \u03b1-glucosidase inhibitory agents.<\/jats:p>","DOI":"10.1021\/acsomega.6c01953","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:26:47Z","timestamp":1787070407000},"page":"50871-50882","source":"Crossref","is-referenced-by-count":0,"title":["Clerodane Diterpenes\nand Structural Modification of\n12-Oxo-Hardwickiic Acid from the Roots of\n                    <i>Croton krabas<\/i>\n                    : \u03b1-Glucosidase Inhibitory Activity, Molecular Docking,\nand ADMET"],"prefix":"10.1021","volume":"11","author":[{"given":"Sunita","family":"Uk-at","sequence":"first","affiliation":[{"name":"Mahasarakham University , , ,","place":["Maha Sarakham, Thailand, 44150"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2931-5917","authenticated-orcid":true,"given":"Mongkol","family":"Nontakitticharoen","sequence":"additional","affiliation":[{"name":"Khon Kaen University , , ,","place":["Khon Kaen, Thailand, 40002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3237-2920","authenticated-orcid":true,"given":"Kwanjai","family":"Kanokmedhakul","sequence":"additional","affiliation":[{"name":"Khon Kaen University , , ,","place":["Khon Kaen, Thailand, 40002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5681-1281","authenticated-orcid":true,"given":"Oue-artorn","family":"Limtragool","sequence":"additional","affiliation":[{"name":"Mahasarakham University , , ,","place":["Maha Sarakham, Thailand, 44150"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"2026090307164522900_cit1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/B978-0-12-809450-1.00009-0","article-title":"\u03b1-Glucosidase enzyme inhibitors\nfrom natural products","author":"Abbas","year":"2017","journal-title":"Discovery Dev. 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Sci."},{"issue":"5","key":"2026090307164522900_cit4","doi-asserted-by":"publisher","DOI":"10.1002\/efd2.112","article-title":"Advances in\nthe natural \u03b1-glucosidase inhibitors","volume":"4","author":"S\u0327o\u0308hretog\u0306lu","year":"2023","journal-title":"eFood"},{"issue":"20","key":"2026090307164522900_cit5","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.3390\/plants11202722","article-title":"Recent updates on phytoconstituent alpha-glucosidase\ninhibitors: An approach towards the treatment of type two diabetes","volume":"11","author":"Kashtoh","year":"2022","journal-title":"Plants"},{"key":"2026090307164522900_cit6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2021.114416","article-title":"A review of biological\nactivities and phytochemistry of six ethnomedicinally important South\nAfrican Croton species","volume":"280","author":"Moremi","year":"2021","journal-title":"J.\nEthnopharmacol."},{"issue":"1","key":"2026090307164522900_cit7","doi-asserted-by":"publisher","DOI":"10.1016\/j.phyplu.2025.100746","article-title":"The Croton genera (Euphorbiaceae) and its richness in chemical\nconstituents with potential range of applications","volume":"5","author":"Coy-Barrera","year":"2025","journal-title":"Phytomedicine Plus"},{"issue":"10","key":"2026090307164522900_cit8","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.3390\/plants12102014","article-title":"Diabetes-Related mechanisms of action\ninvolved in the therapeutic effect of Croton species:\nA systematic review","volume":"12","author":"Espinoza-Herna\u0301ndez","year":"2023","journal-title":"Plants"},{"key":"2026090307164522900_cit9","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2021.104912","article-title":"ent-Clerodane diterpenoids\nfrom the\nstems of Croton krabas","volume":"152","author":"Rajachan","year":"2021","journal-title":"Fitoterapia"},{"issue":"12","key":"2026090307164522900_cit10","doi-asserted-by":"publisher","DOI":"10.1002\/cbdv.202301309","article-title":"A new clerodane\nfrom the leaves of Croton krabas and its cholinesterase\ninhibitory activities","volume":"20","author":"Linphosan","year":"2023","journal-title":"Chem. 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A revision of the structures of crotocaudin and isocrotocaudin","volume":"32","author":"Lourenc\u0327o","year":"1991","journal-title":"Tetrahedron Lett."},{"issue":"18","key":"2026090307164522900_cit28","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1016\/0040-4020(77)80255-X","article-title":"Crotocaudin;\na rearranged labdane\ntype norditerpene from Croton caudatus Geisel","volume":"33","author":"Chatterjee","year":"1977","journal-title":"Tetrahedron"},{"issue":"4","key":"2026090307164522900_cit29","doi-asserted-by":"publisher","first-page":"o1035","DOI":"10.1107\/S1600536805007725","article-title":"ent-(8S,10R)-15,16-epoxy-19-norcleroda-4,11,13(16),14-tetraene-18,6(R):20,12-diolactone\n(isocrotocaudin)","volume":"61","author":"Said","year":"2005","journal-title":"Acta Crystallogr. Sect. E\nStruct. Reports Online"},{"issue":"5","key":"2026090307164522900_cit30","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1021\/np50053a043","article-title":"Chemistry\nin the Annonaceae, XXIV.\nKaurane and kaur-16-ene diterpenes from the stem bark of Annona reticulata","volume":"50","author":"Etse","year":"1987","journal-title":"J. Nat. Prod."},{"issue":"10","key":"2026090307164522900_cit31","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1021\/np50088a014","article-title":"Diterpenes\nof Calibrachoa parviflora","volume":"55","author":"Elliger","year":"1992","journal-title":"J. Nat. Prod."},{"issue":"4","key":"2026090307164522900_cit32","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1590\/S0100-40421998000400004","article-title":"A\u0301cido ent-16alfa,17-diidroxicauran-19-O\u0301ico\nisolado de ouratea semiserrata e os desafios estereoqui\u0301micos\ndos carbonos quirais C-4 e C-16","volume":"21","author":"Velandia","year":"1998","journal-title":"Quim. 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