Discovery of the First-in-Class Dual TSPO/Carbonic Anhydrase Modulators with Promising Neurotrophic Activity
In searching for putative new therapeutic strategies to treat neurodegenerative diseases, the mitochondrial 18 kDa translocator protein (TSPO) and cerebral isoforms of carbonic anhydrase (CA) were exploited as potential targets. Based on the structures of a class of highly affine and selective TSPO ligands and a class of CA activators, both developed by us in recent years, a small library of 2-phenylindole-based dual TSPO/CA modulators was developed, able to bind TSPO and activate CA VII in the low micromolar/submicromolar range. The interaction with the two targets was corroborated by computational studies. Biological investigation on human microglia C20 cells identified derivative <b>3</b> as a promising lead compound worthy of future optimization due to its (i) lack of cytotoxicity, (ii) ability to stimulate TSPO steroidogenic function and activate CA VII, and (iii) ability to effectively upregulate gene expression of the brain-derived neurotrophic factor.
Authors
- Sabrina Taliani (ORCID: https://orcid.org/0000-0001-8675-939X)
- Valeria Poggetti (ORCID: https://orcid.org/0000-0003-1284-4991)
- Simona Daniele (ORCID: https://orcid.org/0000-0001-7391-3087)
- Silvia Salerno (ORCID: https://orcid.org/0000-0002-6072-4698)
- Claudiu T. Supuran (ORCID: https://orcid.org/0000-0003-4262-0323)
- Sabrina Castellano (ORCID: https://orcid.org/0000-0002-7449-3704)
- Elisabetta Barresi (ORCID: https://orcid.org/0000-0002-9814-7195)
- Eleonora Da Pozzo (ORCID: https://orcid.org/0000-0003-4762-8949)
- Lorenzo Germelli (ORCID: https://orcid.org/0000-0002-7318-7545)
- Elisa Angeloni
- Sandro Cosconati (ORCID: https://orcid.org/0000-0002-8900-0968)
- Barbara Costa
- Federico Da Settimo (ORCID: https://orcid.org/0000-0002-7897-7917)
- Giuliana Sarno (ORCID: https://orcid.org/0000-0002-3136-0469)
- Muhammad Waqas (ORCID: https://orcid.org/0000-0001-6115-9689)
- Benito Natale
- Andrea Angeli (ORCID: https://orcid.org/0000-0002-1470-7192)
Institutions
- University of Pisa (IT)
- University of Salerno (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- University of Florence (IT)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1021/acschemneuro.4c00477
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca