title: Design, syntheses and evaluation of 4-oxo-5-cyano thiouracils as SecA inhibitors.
abstract: Protein translocation is essential for bacterial survival and the most important translocation mechanism is the secretion (Sec) pathway in which SecA is a central core driving force. Thus targeting SecA is a promising strategy for developing novel antibacterial therapeutics. Herein, we report the syntheses and evaluation of a series of nearly 60 4-oxo-5-cyano thiouracil derivatives based upon our previously reported core pyrimidine structure. Introduction of polar group such as -N3 and linker groups such as -CH2-O- enhanced the potency several fold. Apart from being potential antibacterial agents, these inhibitors can be indispensable tools for biologists to probe the mechanism of protein translocation via the SecA machinery in bacteria.
authors.affiliation: College of Arts and Sciences, Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Arpana S
authors.initials: AS
authors.lastname: Chaudhary
authors.affiliation: Department of Biology, Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Jinshan
authors.initials: J
authors.lastname: Jin
authors.affiliation: College of Arts and Sciences, Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Weixuan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Biology, Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303, USA. Electronic address: biopct@gsu.edu.
authors.forename: Phang C
authors.initials: PC
authors.lastname: Tai
authors.affiliation: College of Arts and Sciences, Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA. Electronic address: wang@gsu.edu.
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D021381:Protein Transport; D000069816:SEC Translocation Channels; D000081416:SecA Proteins; D013329:Structure-Activity Relationship; D013889:Thiouracil / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D000069816:SEC Translocation Channels; D013889:Thiouracil; D000251:Adenosine Triphosphatases; D000081416:SecA Proteins
keywords: Antimicrobials; Drug resistance; Enzyme inhibitors; Novel drugs; SecA inhibitors