Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of <i>Mycobacterium tuberculosis</i> (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeut...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/2/155 |
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| author | Matteo Mori Giovanni Stelitano Laurent R. Chiarelli Giulia Cazzaniga Arianna Gelain Daniela Barlocco Elena Pini Fiorella Meneghetti Stefania Villa |
| author_facet | Matteo Mori Giovanni Stelitano Laurent R. Chiarelli Giulia Cazzaniga Arianna Gelain Daniela Barlocco Elena Pini Fiorella Meneghetti Stefania Villa |
| 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>Mycobacterium tuberculosis</i> (Mtb) 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 antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of <b>I</b> and <b>II</b>, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (<b>IV</b>–<b>IX</b>), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (<b>IV</b>), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound <b>IV</b> offers promising prospects for future studies on the development of novel agents against mycobacterial infections. |
| first_indexed | 2024-03-09T00:54:40Z |
| format | Article |
| id | doaj.art-9b85a7096bf347e7aa5d0a78f21d473e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T00:54:40Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-9b85a7096bf347e7aa5d0a78f21d473e2023-12-11T16:59:48ZengMDPI AGPharmaceuticals1424-82472021-02-0114215510.3390/ph14020155Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular AgentsMatteo Mori0Giovanni Stelitano1Laurent R. Chiarelli2Giulia Cazzaniga3Arianna Gelain4Daniela Barlocco5Elena Pini6Fiorella Meneghetti7Stefania Villa8Department 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 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, 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>Mycobacterium tuberculosis</i> (Mtb) 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 antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of <b>I</b> and <b>II</b>, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (<b>IV</b>–<b>IX</b>), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (<b>IV</b>), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound <b>IV</b> offers promising prospects for future studies on the development of novel agents against mycobacterial infections.https://www.mdpi.com/1424-8247/14/2/155tuberculosismycobactinsfuransiderophoresdrug designbioisosterism |
| spellingShingle | Matteo Mori Giovanni Stelitano Laurent R. Chiarelli Giulia Cazzaniga Arianna Gelain Daniela Barlocco Elena Pini Fiorella Meneghetti Stefania Villa Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents Pharmaceuticals tuberculosis mycobactins furan siderophores drug design bioisosterism |
| title | Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents |
| title_full | Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents |
| title_fullStr | Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents |
| title_full_unstemmed | Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents |
| title_short | Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents |
| title_sort | synthesis characterization and biological evaluation of new derivatives targeting mbti as antitubercular agents |
| topic | tuberculosis mycobactins furan siderophores drug design bioisosterism |
| url | https://www.mdpi.com/1424-8247/14/2/155 |
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