2. Academic Validation
  3. Discovery of the First-in-Class Dual TSPO/Carbonic Anhydrase Modulators with Promising Neurotrophic Activity

Discovery of the First-in-Class Dual TSPO/Carbonic Anhydrase Modulators with Promising Neurotrophic Activity

  • ACS Chem Neurosci. 2025 Jan 1;16(1):1-15. doi: 10.1021/acschemneuro.4c00477.
Valeria Poggetti 1,  Elisa Angeloni 1,  Lorenzo Germelli 1,  Benito Natale 2,  Muhammad Waqas 2,  Giuliana Sarno 3,  Andrea Angeli 4,  Simona Daniele 1,  Silvia Salerno 1,  Elisabetta Barresi 1,  Sandro Cosconati 2,  Sabrina Castellano 3,  Eleonora Da Pozzo 1,  Barbara Costa 1,  Claudiu T Supuran 4,  Federico Da Settimo 1,  Sabrina Taliani 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
  • 2 DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi, 43, 81100 Caserta, Italy.
  • 3 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Polo Scientifico, University of Florence, Via U. Schiff, 6, Sesto Fiorentino, 50019 Firenze, Italy.
PMID: 39545683 DOI: 10.1021/acschemneuro.4c00477
Abstract

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 3 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.

Keywords

2-phenylindole; carbonic anhydrases; multitarget-directed ligands; neurodegenerative diseases; neuroprotection; translocator protein.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z