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© Research
Publication : European journal of medicinal chemistry

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in European journal of medicinal chemistry - 15 Nov 2020

Jian Y, Merceron R, De Munck S, Forbes HE, Hulpia F, Risseeuw MDP, Van Hecke K, Savvides SN, Munier-Lehmann H, Boshoff HIM, Van Calenbergh S,

Link to Pubmed [PMID] – 32823003

Link to DOI – S0223-5234(20)30631-010.1016/j.ejmech.2020.112659

Eur J Med Chem 2020 Nov; 206(): 112659

As the last enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.

https://pubmed.ncbi.nlm.nih.gov/32823003