Synthesis and structure-activity relationship studies of 2,4-thiazolidinediones and analogous heterocycles as inhibitors of dihydrodipicolinate synthase

Rebecca M Christoff; Tatiana P Soares da Costa; Saadi Bayat; Jessica K Holien; Matthew A Perugini; Belinda M Abbott

doi:10.1016/j.bmc.2021.116518

Synthesis and structure-activity relationship studies of 2,4-thiazolidinediones and analogous heterocycles as inhibitors of dihydrodipicolinate synthase

Bioorg Med Chem. 2021 Dec 15:52:116518. doi: 10.1016/j.bmc.2021.116518. Epub 2021 Nov 12.

Authors

Rebecca M Christoff¹, Tatiana P Soares da Costa², Saadi Bayat¹, Jessica K Holien³, Matthew A Perugini², Belinda M Abbott⁴

Affiliations

¹ Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
² Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
³ School of Science, STEM College, RMIT University, Melbourne, Victoria 3000, Australia.
⁴ Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. Electronic address: b.abbott@latrobe.edu.au.

PMID: 34826680
DOI: 10.1016/j.bmc.2021.116518

Abstract

Dihydrodipicolinate synthase (DHDPS), responsible for the first committed step of the diaminopimelate pathway for lysine biosynthesis, has become an attractive target for the development of new antibacterial and herbicidal agents. Herein, we report the discovery and exploration of the first inhibitors of E. coli DHDPS which have been identified from screening lead and are not based on substrates from the lysine biosynthesis pathway. Over 50 thiazolidinediones and related analogues have been prepared in order to thoroughly evaluate the structure-activity relationships against this enzyme of significant interest.

Keywords: DHDPS inhibitors; Dihydrodipicolinate synthase; Enzyme inhibitors; Thiazolidinediones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Escherichia coli / enzymology
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Hydro-Lyases / antagonists & inhibitors*
Hydro-Lyases / metabolism
Molecular Structure
Structure-Activity Relationship
Thiazolidinediones / chemical synthesis
Thiazolidinediones / chemistry
Thiazolidinediones / pharmacology*

Substances

Enzyme Inhibitors
Heterocyclic Compounds
Thiazolidinediones
2,4-thiazolidinedione
Hydro-Lyases
4-hydroxy-tetrahydrodipicolinate synthase