Tricyclic 1, 5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2). Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Singh, Sheo B.; Kaelin, David E.; Wu, Jin; Miesel, Lynn; Tan, Christopher M.; Black, Todd; Nargund, Ravi; Meinke, Peter T.; Olsen, David B.; Lagrutta, Armando; Lu, Jun; Patel, Sangita; Rickert, Keith W.; Smith, Robert F.; Soisson, Stephen; Sherer, Edward; Joyce, Leo A.; Wei, Changqing; Peng, Xuanjia; Wang, Xiu; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Takano, Hisashi; Shibasaki, Mitsuhito; Yajima, Masanobu; Nishimura, Akinori; Shibata, Takeshi; Fukuda, Yasumichi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 9(2015)
• Page Start: 1831
• Page End: 1835
• Publication Date: 2015-05-01
• Subjects: Antibacterial -- Broad-spectrum -- Bacterial topoisomerase inhibitors -- Gyrase inhibitors -- ParC inhibitors -- Tricyclic-1, 5-naphthyridinone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.044
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1, 5-naphthyridinone left hand side moieties have been described. Compounds with a ( R )-hydroxy-1, 5-naphthyridinone moiety (7 ) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound7 showed intravenous and oral efficacy (ED50 ) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170 μM). In general, lower log D attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1, 5-naphthyridinone based oxabicyclooctane linked NBTIs are described.