Synthesis of sulfamide analogues of deoxthymidine monophosphate as potential inhibitors of mycobacterial cell wall biosynthesis

Kajitha Suthagar; Wanting Jiao; Hélène Munier-Lehmann; Antony J Fairbanks

doi:10.1016/j.carres.2018.01.001

Synthesis of sulfamide analogues of deoxthymidine monophosphate as potential inhibitors of mycobacterial cell wall biosynthesis

Carbohydr Res. 2018 Mar 2:457:32-40. doi: 10.1016/j.carres.2018.01.001. Epub 2018 Jan 11.

Authors

Kajitha Suthagar¹, Wanting Jiao², Hélène Munier-Lehmann³, Antony J Fairbanks⁴

Affiliations

¹ Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, 8140, New Zealand.
² Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, 8140, New Zealand; Ferrier Research Institute, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand.
³ Institut Pasteur, Unité de Chimie et Biocatalyse, 28 rue du Dr Roux, 75724, Paris Cedex 15, France; CNRS UMR3523, 28 rue du Dr Roux, France.
⁴ Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, 8140, New Zealand; Biomolecular Interaction Centre, University of Canterbury, Private Bag 4800, Christchurch, 8140, New Zealand. Electronic address: antony.fairbanks@canterbury.ac.nz.

PMID: 29348046
DOI: 10.1016/j.carres.2018.01.001

Abstract

The recently discovered enzyme Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), which catalyses the phosphorylation of deoxythymidine monophosphate (dTMP) to give deoxythymidine diphosphate (dTDP), is indispensable for the growth and survival of M. tuberculosis as it plays an essential role in DNA synthesis. Inhibition of TMPKmt is an attractive avenue for the development of novel anti-tuberculosis agents. Based on the premise that sulfamide may be a suitable isostere of phosphate, deoxythymidine analogues comprising various substituted sulfamides at C5' were modelled in silico into the active site of TMPKmt (PDB accession code: 1N5K) using induced-fit docking methods. A selection of modelled compounds was synthesized, and their activity as inhibitors of TMPKmt was evaluated. Three compounds showed competitive inhibition of TMPKmt in the micromolar range (10-50 μM). Compounds were tested in vitro for anti-mycobacterial activity against M. smegmatis: three compounds showed weak anti-mycobacterial activity (MIC 250 μg/mL).

Keywords: Carbohydrates; Deoxythymidine; Mycobacteria; Sulfamides; Thymidine monophosphate kinase; Tuberculosis.

MeSH terms

Antitubercular Agents / chemistry*
Antitubercular Agents / pharmacology
Cell Wall / drug effects
Mycobacterium tuberculosis / drug effects
Structure-Activity Relationship
Thymidine / chemistry*
Thymidine / pharmacology

Substances

Antitubercular Agents
Thymidine