Evaluation of ketoclomazone and its analogues as inhibitors of 1-deoxy-d-xylulose 5-phosphate synthases and other thiamine diphosphate (ThDP)-dependent enzymes

• Published in: MedChemComm Vol. 15; no. 5; pp. 1773 - 1781
• Main Authors: Chan, Alex H. Y., Ho, Terence C. S., Fathoni, Imam, Hamid, Rawia, Hirsch, Anna K. H., Saliba, Kevin J., Leeper, Finian J.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 22.05.2024; Royal Society of Chemistry; RSC
• Subjects: Antibacterial agents; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; D-Xylulose 5-phosphate; Herbicides; Inhibitors; Life Sciences & Biomedicine; Parasites; Pharmacology & Pharmacy; Science & Technology; Terpenes; Thiamine; Thiamine diphosphate; Xylulose; 1-DEOXY-D-XYLULOSE-5-PHOSPHATE SYNTHASE; MECHANISM; ISOPRENOID BIOSYNTHESIS; PATHWAY; INSIGHTS
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/d4md00083h

Most pathogenic bacteria, apicomplexan parasites and plants rely on the methylerythritol phosphate (MEP) pathway to obtain precursors of isoprenoids. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS), a thiamine diphosphate (ThDP)-dependent enzyme, catalyses the first and rate-limiting step of the MEP pathway. Due to its absence in humans, DXPS is considered as an attractive target for the development of anti-infectious agents and herbicides. Ketoclomazone is one of the earliest reported inhibitors of DXPS and antibacterial and herbicidal activities have been documented. This study investigated the activity of ketoclomazone on DXPS from various species, as well as the broader ThDP-dependent enzyme family. To gain further insights into the inhibition, we have prepared analogues of ketoclomazone and evaluated their activity in biochemical and computational studies. Our findings support the potential of ketoclomazone as a selective antibacterial agent.