Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of <i>M. tuberculosis</i> (<i>Mtb</i>) have developed resistance against most of the established anti-TB drugs, new t...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/8/992 |
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| author | Matteo Mori Giovanni Stelitano Anna Griego Laurent R. Chiarelli Giulia Cazzaniga Arianna Gelain Elena Pini Marina Camera Paola Canzano Andrea Fumagalli Edoardo Scarpa Chiara Cordiglieri Loris Rizzello Stefania Villa Fiorella Meneghetti |
| author_facet | Matteo Mori Giovanni Stelitano Anna Griego Laurent R. Chiarelli Giulia Cazzaniga Arianna Gelain Elena Pini Marina Camera Paola Canzano Andrea Fumagalli Edoardo Scarpa Chiara Cordiglieri Loris Rizzello Stefania Villa Fiorella Meneghetti |
| author_sort | Matteo Mori |
| collection | DOAJ |
| description | Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of <i>M. tuberculosis</i> (<i>Mtb</i>) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (<b>I</b>), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, <b>1f</b> emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs. |
| first_indexed | 2024-03-09T09:51:10Z |
| format | Article |
| id | doaj.art-a89679d5dd8a4796a26f8260240379b5 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T09:51:10Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-a89679d5dd8a4796a26f8260240379b52023-12-02T00:09:03ZengMDPI AGPharmaceuticals1424-82472022-08-0115899210.3390/ph15080992Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial InfectionsMatteo Mori0Giovanni Stelitano1Anna Griego2Laurent R. Chiarelli3Giulia Cazzaniga4Arianna Gelain5Elena Pini6Marina Camera7Paola Canzano8Andrea Fumagalli9Edoardo Scarpa10Chiara Cordiglieri11Loris Rizzello12Stefania Villa13Fiorella Meneghetti14Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Via A. Ferrata 9, 27100 Pavia, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Via A. Ferrata 9, 27100 Pavia, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyCentro Cardiologico Monzino, Istituto di Ricerca e Cura a Carattere Scientifico, Via C. Parea 4, 20138 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyNational Institute of Molecular Genetic (INGM), Via F. Sforza 35, 20122 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyTuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of <i>M. tuberculosis</i> (<i>Mtb</i>) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (<b>I</b>), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, <b>1f</b> emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs.https://www.mdpi.com/1424-8247/15/8/992tuberculosismycobactinsfuransiderophoresdrug developmentdrug resistance |
| spellingShingle | Matteo Mori Giovanni Stelitano Anna Griego Laurent R. Chiarelli Giulia Cazzaniga Arianna Gelain Elena Pini Marina Camera Paola Canzano Andrea Fumagalli Edoardo Scarpa Chiara Cordiglieri Loris Rizzello Stefania Villa Fiorella Meneghetti Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections Pharmaceuticals tuberculosis mycobactins furan siderophores drug development drug resistance |
| title | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
| title_full | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
| title_fullStr | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
| title_full_unstemmed | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
| title_short | Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections |
| title_sort | synthesis and assessment of the in vitro and ex vivo activity of salicylate synthase mbti inhibitors as new candidates for the treatment of mycobacterial infections |
| topic | tuberculosis mycobactins furan siderophores drug development drug resistance |
| url | https://www.mdpi.com/1424-8247/15/8/992 |
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