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Structure-based design of multitargeting ChEs-MAO B inhibitors based on phenyl ring bioisosteres: AChE/BChE selectivity switch and drug-like characterization

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  • معلومة اضافية
    • Contributors:
      La Spada, Gabriella; Miniero, Daniela Valeria; Rullo, Mariagrazia; Cipolloni, Marco; Delre, Pietro; Colliva, Carolina; Colella, Marco; Leonetti, Francesco; Liuzzi, Grazia Maria; Mangiatordi, Giuseppe Felice; Giacchè, Nicola; Pisani, Leonardo
    • الموضوع:
      2024
    • Collection:
      Università degli Studi di Bari Aldo Moro: CINECA IRIS
    • نبذة مختصرة :
      A structure-based drug design approach was focused on incorporating phenyl ring heterocyclic bioisosteres into coumarin derivative 1, previously reported as potent dual AChE-MAO B inhibitor, with the aim of improving drug-like features. Structure-activity relationships highlighted that bioisosteric rings were tolerated by hMAO B enzymatic cleft more than hAChE. Interestingly, linker homologation at the basic nitrogen enabled selectivity to switch from hAChE to hBChE. In the present work, we identified thiophene-based isosteres 7 and 15 as dual AChE-MAO B (IC50 = 261 and 15 nM, respectively) and BChE-MAO B (IC50 = 375 and 20 nM, respectively) inhibitors, respectively. Both 7 and 15 were moderately water-soluble and membrane-permeant agents by passive diffusion (PAMPA-HDM). Moreover, they were able to counteract oxidative damage induced by both H2O2 and 6-OHDA in SH-SY5Y cells and predicted to penetrate into CNS in a cell-based model mimicking blood-brain barrier. Molecular dynamics (MD) simulations shed light on key differences in AChE and BChE recognition processes promoted by the basic chain homologation from 7 to 15.
    • Relation:
      info:eu-repo/semantics/altIdentifier/wos/WOS:001249456700001; volume:274; journal:EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; https://hdl.handle.net/11586/479540
    • الرقم المعرف:
      10.1016/j.ejmech.2024.116511
    • الدخول الالكتروني :
      https://hdl.handle.net/11586/479540
      https://doi.org/10.1016/j.ejmech.2024.116511
    • Rights:
      info:eu-repo/semantics/openAccess
    • الرقم المعرف:
      edsbas.B83C4321