Author: Cocorullo, Mario ; Zanoni, Giuseppe ; Pini, Elena ; Porta, Alessio ; Meneghetti, Fiorella ; Moschetti, Giorgia ; Villa, Stefania ; Scarpa, Edoardo ; Griego, Anna ; Stelitano, Giovanni ; Battaglia, Giuseppe ; Casali, Emanuele ; Tuccinardi, Tiziano ; Batalha, Íris L. ; Rizzello, Loris ; Chiarelli, Laurent R. ; Cazzaniga, Giulia ; Muzzioli, Stefano ; Mori, Matteo ; Tresoldi, Andrea

The urgent need for safer and innovative antitubercular agents remains a priority for the scientific community. In pursuit of this goal, we designed and evaluated novel 5-phenylfuran-2-carboxylic acid derivatives targeting Mycobacterium tuberculosis (Mtb) salicylate synthase (MbtI), a key enzyme, absent in humans, that plays a crucial role in Mtb virulence. Several potent MbtI inhibitors demonstrating significant antitubercular activity and a favorable safety profile were identified. Structure-guided optimization yielded 5-(3-cyano-5-isobutoxyphenyl)furan-2-carboxylic acid (1e), which exhibited strong MbtI inhibition (IC₅₀ = 11.2 μM) and a promising in vitro antitubercular activity (MIC₉₉ = 32 μM against M. bovis BCG). Esters of 1e were effectively loaded into poly(2-methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes (POs) and delivered to intracellular mycobacteria, resulting in reduced Mtb viability. This study provides a foundation for the use of POs in the development of future MbtI-targeted therapies for tuberculosis.

09 Jul 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design

Q1 · MEDICINE

Article

Author: Porta, Alessio ; Meneghetti, Fiorella ; Beretta, Giangiacomo ; Tuccinardi, Tiziano ; Stelitano, Giovanni ; Gelain, Arianna ; Chiarelli, Laurent R. ; Pini, Elena ; Villa, Stefania ; Poli, Giulio ; Bellinzoni, Marco ; Sammartino, José C. ; Mori, Matteo

The Mg²⁺-dependent Mycobacterium tuberculosis salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure-activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (10, K_i = 4 μM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg²⁺-independent binding mode. We also investigated the role of the Mg²⁺ cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg²⁺-salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.

01 Jan 2019·Journal of Enzyme Inhibition and Medicinal ChemistryQ2 · MEDICINE

New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents

Q2 · MEDICINE

ArticleOA

Author: Chiarelli, Laurent R. ; Tuccinardi, Tiziano ; Sammartino, Josè Camilla ; Poli, Giulio ; Mori, Matteo ; Pini, Elena ; Caligiuri, Isabella ; Stelitano, Giovanni ; Beretta, Giangiacomo ; Meneghetti, Fiorella ; Barlocco, Daniela ; Gelain, Arianna ; Lapillo, Margherita ; Rizzolio, Flavio ; Costantino, Luca ; Bellinzoni, Marco ; Villa, Stefania

Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a K_i of 8.8 µM and its antimycobacterial activity (MIC⁹⁹ = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	Italy	University of Insubria	03 Mar 2025

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