Comprehensive experimental and computational evaluation of novel linagliptin-analogues: Synthesis, DFT calculations, molecular modeling, and in vitro anticancer/antioxidant activities

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dc.contributor.authorDilek, Omer
dc.contributor.authorBahar, Dilek
dc.contributor.authorYesil, Tolga Acar
dc.contributor.authorOzkara, Yagmur
dc.contributor.authorTilki, Tahir
dc.date.accessioned2026-04-25T14:19:56Z
dc.date.available2026-04-25T14:19:56Z
dc.date.issued2026
dc.departmentSinop Üniversitesi
dc.description.abstractRecent evidence suggests that linagliptin and its structural derivatives exhibit biological activities beyond glycemic control, highlighting the linagliptin scaffold as a promising platform for multifunctional drug design. In this study, eight novel linagliptin-based azo-imine derivatives (3a-h) were designed, synthesized, and structurally characterized, with the stereochemistry of representative compound 3e confirmed by 2D NMR. Computational analyses (DFT, molecular docking, and molecular dynamics simulations) were employed to support electronic structure elucidation and ligand-protein interaction stability. Specifically, 250 ns molecular dynamics simulations confirmed that the 6XFP-3h complex maintains high structural stability and thermodynamic equilibration throughout the trajectory. All derivatives displayed moderate antioxidant activity (TEAC = 0.46-0.84). Antiproliferative effects were evaluated against A549 and DLD1 cancer cell lines, with WI-38 fibroblasts used to assess selectivity. Compound 3h exhibited the highest potency, with IC50 values of 0.66 & micro;M (A549) and 0.29 & micro;M (DLD1), while compounds 3d and 3e showed cytotoxicity comparable to cisplatin. Selectivity index analysis revealed moderate but discernible cancer cell preference, with compound 3h demonstrating the most favorable selectivity toward DLD1 cells (SI = 3.62). These results suggest that compound 3h represents a prioritized candidate within this series and support linagliptin-based azo-imine derivatives as a tractable framework for further structure-activity relationship optimization.
dc.identifier.doi10.1016/j.compbiolchem.2026.108999
dc.identifier.issn1476-9271
dc.identifier.issn1476-928X
dc.identifier.pmid41797067
dc.identifier.scopus2-s2.0-105032064561
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1016/j.compbiolchem.2026.108999
dc.identifier.urihttps://hdl.handle.net/11486/8262
dc.identifier.volume123
dc.identifier.wosWOS:001712506300001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier Sci Ltd
dc.relation.ispartofComputational Biology and Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WOS_20260420
dc.subjectLinagliptin
dc.subjectAzo-Imine
dc.subject2D NMR
dc.subjectCytotoxicity
dc.subjectAntioxidant
dc.subjectIn silico studies
dc.titleComprehensive experimental and computational evaluation of novel linagliptin-analogues: Synthesis, DFT calculations, molecular modeling, and in vitro anticancer/antioxidant activities
dc.typeArticle

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