New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies

Pini, Elena; Poli, Giulio; Tuccinardi, Tiziano; Chiarelli, Laurent Roberto; Mori, Matteo; Gelain, Arianna; Costantino, Luca; Villa, Stefania; Meneghetti, Fiorella; Barlocco, Daniela

doi:10.3390/molecules23071506

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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

Laurent Roberto Chiarelli

¹,

⁴,

¹,

^1,*

and

Daniela Barlocco

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy

Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy

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

Author to whom correspondence should be addressed.

^†

These authors contributed equally.

Molecules 2018, 23(7), 1506; https://doi.org/10.3390/molecules23071506

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)

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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-Text

Keywords: antimycobacterial agent; siderophore; mycobactin; iron; consensus docking; chorismate; MD simulation

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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. https://doi.org/10.3390/molecules23071506

AMA Style

Pini E, Poli G, Tuccinardi T, Chiarelli LR, 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(7):1506. https://doi.org/10.3390/molecules23071506

Chicago/Turabian Style

Pini, Elena, Giulio Poli, Tiziano Tuccinardi, Laurent Roberto Chiarelli, Matteo Mori, Arianna Gelain, Luca Costantino, Stefania Villa, Fiorella Meneghetti, and Daniela Barlocco. 2018. "New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies" Molecules 23, no. 7: 1506. https://doi.org/10.3390/molecules23071506

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New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies

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