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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalMolecules
Volume23
Issue number7
DOIs
Publication statusPublished - Jun 21 2018

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Molecular modeling
Salicylates
Iron Chelating Agents
Antitubercular Agents
Lead compounds
Derivatives
Biosynthesis
Enzymes
mycobactins

Keywords

  • Amino Acid Motifs
  • Antitubercular Agents/chemical synthesis
  • Bacterial Proteins/antagonists & inhibitors
  • Catalytic Domain
  • Chorismic Acid/chemistry
  • Chromans/chemical synthesis
  • Enzyme Inhibitors/chemical synthesis
  • Gene Expression
  • Kinetics
  • Lyases/antagonists & inhibitors
  • Molecular Docking Simulation
  • Mycobacterium tuberculosis/chemistry
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Recombinant Proteins/chemistry
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thermodynamics

Cite this

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.

In: Molecules, Vol. 23, No. 7, 21.06.2018.

Research output: Contribution to journalArticle

Pini, Elena ; Poli, Giulio ; Tuccinardi, Tiziano ; Chiarelli, Laurent Roberto ; Mori, Matteo ; Gelain, Arianna ; Costantino, Luca ; Villa, Stefania ; Meneghetti, Fiorella ; Barlocco, Daniela. / New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI) : Preliminary Biological Evaluation and Molecular Modeling Studies. In: Molecules. 2018 ; Vol. 23, No. 7.
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KW - Enzyme Inhibitors/chemical synthesis

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