Design, synthesis and antimicrobial activities of thiouracil derivatives containing triazolo-thiadiazole as SecA inhibitors

• Published in: European journal of medicinal chemistry 2017-02, Vol.127, p.159-165
• Main Authors: Cui, Penglei, Li, Xiaoliu, Zhu, Mengyuan, Wang, Binghe, Liu, Jing, Chen, Hua
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Bacillus subtilis - drug effects; Bacillus subtilis - enzymology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Chemistry Techniques, Synthetic; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Molecular Docking Simulation; Molecular simulation; Protein Conformation; SEC Translocation Channels - antagonists & inhibitors; SEC Translocation Channels - chemistry; SEC Translocation Channels - metabolism; SecA inhibitors; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Thiadiazoles - chemistry; Thiouracil; Thiouracil - chemical synthesis; Thiouracil - chemistry; Thiouracil - metabolism; Thiouracil - pharmacology; Triazoles - chemistry; Triazolo-thiadiazole
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.12.053

A series of novel thiouracil derivatives containing a triazolo-thiadiazole moiety (7a-7l) have been synthesized by structural modifications on a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7d and 7g were also tested for their inhibitory activities against SecA ATPase due to their promising antimicrobial activities. The inhibitory activity of compound 7d was found to be higher than that of 2. Molecular docking work suggests that compound 7d might bind at a pocket close to the ATPase ATP-binding domain. A series of novel thiouracil derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications of a lead SecA inhibitor. Compound 7d showed high inhibitory activity against the SecA ATPase. [Display omitted] •Novel thiouracil derivatives containing a triazolo-thiadiazole moiety were synthesized.•Most of the compounds showed strong antibacterial activities.•Compound 7d significantly inhibited SecA ATPase activity.•Compound 7d binds at a pocket close to the ATP-binding domain.•The triazole-thiadiazole moiety was of benefit to their SecA inhibitory activity.