Design, synthesis and antibacterial activities of thiouracil derivatives containing acyl thiourea as SecA inhibitors

Penglei Cui; Xiaoliu Li; Mengyuan Zhu; Binghe Wang; Jing Liu; Hua Chen

doi:10.1016/j.bmcl.2016.11.060

Design, synthesis and antibacterial activities of thiouracil derivatives containing acyl thiourea as SecA inhibitors

Bioorg Med Chem Lett. 2017 May 15;27(10):2234-2237. doi: 10.1016/j.bmcl.2016.11.060. Epub 2016 Nov 23.

Authors

Penglei Cui¹, Xiaoliu Li², Mengyuan Zhu³, Binghe Wang³, Jing Liu⁴, Hua Chen⁵

Affiliations

¹ Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China; College of Science, Agricultural University of Hebei, Baoding 071001, China.
² Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China. Electronic address: lixl@hbu.cn.
³ Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302-4098, USA.
⁴ College of Veterinary Medicine, Agricultural University of Hebei, Baoding 071001, China.
⁵ Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China. Electronic address: hua-todd@163.com.

PMID: 28041832
DOI: 10.1016/j.bmcl.2016.11.060

Abstract

A series of novel thiouracil derivatives containing an acyl thiourea moiety (7a-7x) have been synthesized by structural modification of a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7c, 7m, 7u, 7v exhibited promising activities against above bacteria. Such four compounds were further tested for their inhibitory activity against SecA ATPase, and the results showed that compounds 7c and 7u had higher inhibitory activities than that of compound 2. Molecular docking work suggests that compound 7u might bind at a pocket close to the ATPase ATP-binding domain.

Keywords: Acyl thiourea; Antibacterial activity; Molecular simulation; SecA inhibitors; Thiouracil.

MeSH terms

Adenosine Triphosphatases / antagonists & inhibitors*
Adenosine Triphosphatases / metabolism
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Bacillus amyloliquefaciens / drug effects
Bacillus subtilis / drug effects
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Binding Sites
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Microbial Sensitivity Tests
Molecular Docking Simulation
Protein Structure, Tertiary
SEC Translocation Channels / antagonists & inhibitors*
SEC Translocation Channels / metabolism
SecA Proteins
Staphylococcus aureus / drug effects
Thiouracil / analogs & derivatives*
Thiouracil / chemical synthesis
Thiouracil / pharmacology

Substances

Anti-Bacterial Agents
Bacterial Proteins
Enzyme Inhibitors
SEC Translocation Channels
Thiouracil
Adenosine Triphosphatases
SecA Proteins