2. Academic Validation
  3. New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

New Pyrimidine and Pyridine Derivatives as Multitarget Cholinesterase Inhibitors: Design, Synthesis, and In Vitro and In Cellulo Evaluation

  • ACS Chem Neurosci. 2021 Nov 3;12(21):4090-4112. doi: 10.1021/acschemneuro.1c00485.
Martina Bortolami 1,  Fabiana Pandolfi 1,  Valeria Tudino 2,  Antonella Messore 2,  Valentina Noemi Madia 2,  Daniela De Vita 3,  Roberto Di Santo 4,  Roberta Costi 4,  Isabella Romeo 5 6,  Stefano Alcaro 5 6,  Marisa Colone 7,  Annarita Stringaro 7,  Alba Espargaró 8,  Raimon Sabatè 8,  Luigi Scipione 2
Affiliations

Affiliations

  • 1 Department of Scienze di Base e Applicate per l'Ingegneria, Sapienza University of Rome, via Castro Laurenziano 7, I-00161 Rome, Italy.
  • 2 Department of Chimica e Tecnologia del Farmaco, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 3 Department of Environmental Biology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 4 Istituto Pasteur, Fondazione Cenci Bolognetti, Department of Chemistry and Technology of Drug, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 5 Net4Science s.r.l., Campus universitario ″S. Venuta″, Viale Europa, 88100 Catanzaro, Italy.
  • 6 Dipartimento di Scienze della Salute, Università ″Magna Græcia″ di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
  • 7 National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 00161 Rome, Italy.
  • 8 Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avda. Joan XXIII, 27-31 Barcelona, Catalonia, Spain.
PMID: 34652128 DOI: 10.1021/acschemneuro.1c00485
Abstract

A new series of pyrimidine and pyridine diamines was designed as dual binding site inhibitors of cholinesterases (ChEs), characterized by two small aromatic moieties separated by a diaminoalkyl flexible linker. Many compounds are mixed or uncompetitive acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with compound 9 being the most active on Electrophorus electricus AChE (EeAChE) (Ki = 0.312 μM) and compound 22 on equine BChE (eqBChE) (Ki = 0.099 μM). Molecular docking and molecular dynamic studies confirmed the interaction mode of our compounds with the enzymatic active site. UV-vis spectroscopic studies showed that these compounds can form complexes with Cu2+ and Fe3+ and that compounds 18, 20, and 30 have antioxidant properties. Interestingly, some compounds were also able to reduce Aβ42 and tau aggregation, with compound 28 being the most potent (22.3 and 17.0% inhibition at 100 μM on Aβ42 and tau, respectively). Moreover, the most active compounds showed low cytotoxicity on a human brain cell line and they were predicted as BBB-permeable.

Keywords

acetylcholinesterase inhibitors; amyloid aggregation; antioxidant; butyrylcholinesterase inhibitors; metal chelation; multifunctional compounds; tau aggregation.

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