2. Academic Validation
  3. Design, synthesis and antibacterial activity against pathogenic mycobacteria of conjugated hydroxamic acids, hydrazides and O-alkyl/O-acyl protected hydroxamic derivatives

Design, synthesis and antibacterial activity against pathogenic mycobacteria of conjugated hydroxamic acids, hydrazides and O-alkyl/O-acyl protected hydroxamic derivatives

  • Bioorg Med Chem Lett. 2022 May 15:64:128692. doi: 10.1016/j.bmcl.2022.128692.
Vasiliki Mavrikaki 1,  Alexandros Pagonis 2,  Isabelle Poncin 3,  Ivy Mallick 3,  Stéphane Canaan 3,  Victoria Magrioti 2,  Jean-François Cavalier 4
Affiliations

Affiliations

  • 1 Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. Electronic address: [email protected].
  • 2 Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
  • 3 Aix-Marseille Univ, CNRS, LISM, IMM FR3479, Marseille, France.
  • 4 Aix-Marseille Univ, CNRS, LISM, IMM FR3479, Marseille, France. Electronic address: [email protected].
PMID: 35307568 DOI: 10.1016/j.bmcl.2022.128692
Abstract

With the aim to discover new antituberculous molecules, three novel series of 23 hydroxamic acids, 13 hydrazides, and 9O-alkyl/O-acyl protected hydroxamic acid derivatives have been synthesized, and fully characterized by spectral 1H NMR, 13C NMR, HRMS) analysis. These compounds were further biologically screened for their in vitro Antibacterial activities against three pathogenic mycobacteria - M. abscessus S and R, M. marinum, and M. tuberculosis - as well as for their toxicity towards murine macrophages by the resazurin microtiter assay (REMA). Among the 45 derivatives, 17 compounds (3 hydroxamic acids, 9 hydrazides, and 5O-alkyl/O-acyl protected hydroxamic acids) were nontoxic against murine macrophages. When tested for their Antibacterial activity, hydroxamic acid 9 h was found to be the most potent inhibitor against M. abscessus S and R only. Regarding hydrazide series, only 7h was active against M. abscessus R, M. marinum and M. tuberculosis; while the O-acyl protected hydroxamic acid derivatives 14d and 15d displayed promising Antibacterial activity against both M. marinum and M. tuberculosis. Since such hydroxamic- and hydrazide-chelating groups have been reported to impair the activity of the peptide deformylase, in silico molecular docking studies in M. tuberculosis peptide deformylase enzyme active site were further performed with 7h in order to predict the possible interaction mode and binding energy of this molecule at the molecular level.

Keywords

Antibacterial; Antituberculous compounds; Hydrazides; Hydroxamic acids; Mycobacterium tuberculosis.

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