Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors

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dc.authoridDemir, Yeliz/0000-0003-3216-1098
dc.authoridEce, Abdulilah/0000-0002-3087-5145
dc.authoridTurkes, Cuneyt/0000-0002-2932-2789
dc.authoridTAHTACI, HAKAN/0000-0002-1557-6315
dc.contributor.authorAskin, Sercan
dc.contributor.authorTahtaci, Hakan
dc.contributor.authorTurkes, Cuneyt
dc.contributor.authorDemir, Yeliz
dc.contributor.authorEce, Abdulilah
dc.contributor.authorCiftci, Gulsen Akalsn
dc.contributor.authorBeydemir, Sukru
dc.date.accessioned2024-09-29T15:55:04Z
dc.date.available2024-09-29T15:55:04Z
dc.date.issued2021
dc.departmentKarabük Üniversitesien_US
dc.description.abstractImidazole and thiadiazole derivatives display an extensive application in pharmaceutical chemistry, and they have been investigated as bioactive molecules for medicinal chemistry purposes. Classical carbonic anhydrase (CA) inhibitors are based on sulfonamide groups, but inhibiting all CA isoforms nonspecifically, thereby causing undesired side effects, is the main drawback of these types of inhibitors. Here we reported an investigation of novel 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (9a-k, 10a, and 11a) and 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (12a-20a) that do not possess the zinc-binding sulfonamide group for the inhibition of human carbonic anhydrase (hCA, EC 4.2.1.1) I and II isoforms and also of acetylcholinesterase (AChE, EC 3.1.1.7). Imidazo[2,1-b][1,3,4]thiadiazoles demonstrated low nanomolar inhibitory activity against hCA I, hCA II, and AChE (KIs are in the range of 23.44-105.50 nM, 10.32-104.70 nM, and 20.52-54.06 nM, respectively). Besides, compound 9b inhibit hCA I up to 18-fold compared to acetazolamide, while compound 10a has a 5-fold selectivity towards hCA II. The synthesized compounds were also evaluated for their cytotoxic effects on the L929 mouse fibroblast cell line. Molecular docking simulations were performed to elucidate these inhibitors' potential binding modes against hCA I and II isoforms and AChE. The novel compounds reported here can represent interesting lead compounds, and the results presented here might provide further structural guidance to discover and design more potent hCA and AChE inhibitors.en_US
dc.description.sponsorshipKarabuk University [KBUBAP18YL165]; Erzincan Binali Yldrm University [TSA2020729]; Ardahan University [2019007]; Anadolu University [1610S681]en_US
dc.description.sponsorshipThis work was supported by the Research Fund of Karabuk University (grant number KBUBAP18YL165) , the Research Fund of Erzincan Binali Yldrm University (grant number TSA2020729) , the Research Fund of Ardahan University (grant number 2019007) , and the Research Fund of Anadolu University (grant number 1610S681) .en_US
dc.identifier.doi10.1016/j.bioorg.2021.105009
dc.identifier.issn0045-2068
dc.identifier.issn1090-2120
dc.identifier.pmid34052739en_US
dc.identifier.scopus2-s2.0-85106605026en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1016/j.bioorg.2021.105009
dc.identifier.urihttps://hdl.handle.net/20.500.14619/4435
dc.identifier.volume113en_US
dc.identifier.wosWOS:000663790900010en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAcademic Press Inc Elsevier Scienceen_US
dc.relation.ispartofBioorganic Chemistryen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectCarbonic anhydraseen_US
dc.subjectAcetylcholinesteraseen_US
dc.subjectImidazoen_US
dc.subject[2,1-b][1,3,4]thiadiazoleen_US
dc.subjectIn silico studyen_US
dc.titleDesign, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitorsen_US
dc.typeArticleen_US

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