Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease

Pedro de Sena M Pinheiro; Francesca de Chirico; Manuela Loi; Stefania Trazzi; Elisabetta Ciani; Daniel Alencar Rodrigues; Marina Amaral Alves; Lídia Moreira Lima; Andrea Milelli; Barbara Monti; Carlos Alberto Manssour Fraga; Maria Laura Bolognesi

doi:10.1016/j.ejmech.2025.117868

Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease

Eur J Med Chem. 2025 Jun 13:296:117868. doi: 10.1016/j.ejmech.2025.117868. Online ahead of print.

Affiliations

¹ Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil. Electronic address: pedro.pinheiro@icb.ufrj.br.
² Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova, 16132, Italy.
³ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
⁴ School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland, 1st Floor Ardilaun House Block B 111 St Stephen's Green, Dublin 2, Ireland.
⁵ Walter Mors Institute of Research on Natural Products, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
⁶ Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
⁷ Department for Life Quality Studies, University of Bologna, Rimini, Italy.
⁸ Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
⁹ Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
¹⁰ Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it.

PMID: 40541115
DOI: 10.1016/j.ejmech.2025.117868

Abstract

The discovery of new therapeutic agents for the treatment of neurodegenerative diseases-particularly Alzheimer's disease (AD) -remains one of the most challenging areas in medicinal chemistry. Given the multifactorial nature of these disorders, the rational design of multitarget-directed ligands (MTDLs) is gaining increasing attention, underscoring the importance of exploring novel target combinations. In this study, we report the design of the first-in-class multitarget compounds that function as dual GPR40 agonists and HDAC6 inhibitors-a novel strategy aimed at modulating neuroinflammation in AD. Among them, compound 4e exhibited potent activity, with an EC₅₀ of 22 nM for GPR40 activation and an IC₅₀ of 73 nM for HDAC6 inhibition. This balanced dual profile was corroborated in cell-based assays, where compound 4e significantly increased acetylated tubulin and ERK phosphorylation levels in SH-SY5Y cells. Furthermore, compound 4e demonstrated immunomodulatory effects on microglia, highlighting its potential as a chemical starting point for targeting neuroinflammation and, ultimately, neurodegeneration.

Keywords: Dementia; Dual compounds; Free fatty acid receptor 1; Histone deacetylase 6; Multitarget; Neurodegeneration; Neuroinflammation.