Molecules 2018, 23(7), 1506; https://doi.org/10.3390/molecules23071506
New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies
Elena Pini 1,†
, Giulio Poli 2,†, Tiziano Tuccinardi 2, Laurent Roberto Chiarelli 3, Matteo Mori 1, Arianna Gelain 1, Luca Costantino 4, Stefania Villa 1, Fiorella Meneghetti 1,*
and Daniela Barlocco 1
, Giulio Poli 2,†, Tiziano Tuccinardi 2, Laurent Roberto Chiarelli 3, Matteo Mori 1, Arianna Gelain 1, Luca Costantino 4, Stefania Villa 1, Fiorella Meneghetti 1,*
and Daniela Barlocco 11
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy
2
Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy
3
Dipartimento di Biologia e Biotecnologie “Lazzaro Spallanzani”, Università degli Studi di Pavia, via Ferrata 9, 27100 Pavia, Italy
4
Dipartimento Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, via Campi 103, 41121 Modena, Italy
†
These authors contributed equally.
*
Author to whom correspondence should be addressed.
Received: 22 May 2018 / Revised: 15 June 2018 / Accepted: 19 June 2018 / Published: 21 June 2018
(This article belongs to the Special Issue Application of Computational Methods in Drug Design)
Abstract
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. View Full-TextKeywords:
antimycobacterial agent; siderophore; mycobactin; iron; consensus docking; chorismate; MD simulation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Pini, E.; Poli, G.; Tuccinardi, T.; Chiarelli, L.R.; Mori, M.; Gelain, A.; Costantino, L.; Villa, S.; Meneghetti, F.; Barlocco, D. New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies. Molecules 2018, 23, 1506.
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