New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies
Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron,...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-06-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/7/1506 |
| _version_ | 1818262759298564096 |
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| author | Elena Pini Giulio Poli Tiziano Tuccinardi Laurent Roberto Chiarelli Matteo Mori Arianna Gelain Luca Costantino Stefania Villa Fiorella Meneghetti Daniela Barlocco |
| author_facet | Elena Pini Giulio Poli Tiziano Tuccinardi Laurent Roberto Chiarelli Matteo Mori Arianna Gelain Luca Costantino Stefania Villa Fiorella Meneghetti Daniela Barlocco |
| author_sort | Elena Pini |
| collection | DOAJ |
| description | Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies. |
| first_indexed | 2024-12-12T19:08:14Z |
| format | Article |
| id | doaj.art-9ae7d197351a4e6e8bd277cbc651bdc8 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-12T19:08:14Z |
| publishDate | 2018-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-9ae7d197351a4e6e8bd277cbc651bdc82022-12-22T00:14:54ZengMDPI AGMolecules1420-30492018-06-01237150610.3390/molecules23071506molecules23071506New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling StudiesElena Pini0Giulio Poli1Tiziano Tuccinardi2Laurent Roberto Chiarelli3Matteo Mori4Arianna Gelain5Luca Costantino6Stefania Villa7Fiorella Meneghetti8Daniela Barlocco9Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, ItalyDipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, ItalyDipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, ItalyDipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani”, Università degli Studi di Pavia, via Ferrata 9, 27100 Pavia, ItalyDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, ItalyDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, ItalyDipartimento Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, via Campi 103, 41121 Modena, ItalyDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, ItalyDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, ItalyDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, ItalyTuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.http://www.mdpi.com/1420-3049/23/7/1506antimycobacterial agentsiderophoremycobactinironconsensus dockingchorismateMD simulation |
| spellingShingle | Elena Pini Giulio Poli Tiziano Tuccinardi Laurent Roberto Chiarelli Matteo Mori Arianna Gelain Luca Costantino Stefania Villa Fiorella Meneghetti Daniela Barlocco New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies Molecules antimycobacterial agent siderophore mycobactin iron consensus docking chorismate MD simulation |
| title | New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies |
| title_full | New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies |
| title_fullStr | New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies |
| title_full_unstemmed | New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies |
| title_short | New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies |
| title_sort | new chromane based derivatives as inhibitors of mycobacterium tuberculosis salicylate synthase mbti preliminary biological evaluation and molecular modeling studies |
| topic | antimycobacterial agent siderophore mycobactin iron consensus docking chorismate MD simulation |
| url | http://www.mdpi.com/1420-3049/23/7/1506 |
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