Structure activity relationship of substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-4)

Abstract

Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bacterial topoisomerase inhibitors (NBTIs) are new class of broad-spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV. This class of inhibitors binds to an alternative binding site relative to fluoroquinolones and shows no cross-resistance to quinolones. NBTIs consist of three structural motifs. A structure activity relationship of the left hand motif 1,5-naphthyridine of oxabicyclooctane-linked NBTIs is described. Fifty five compounds were evaluated against a panel of key Gram-positive and Gram-negative strains of bacteria, as well as for hERG activity and five compounds were tested for in vivo efficacy in murine model of Staphylococcus aureus infection. These studies suggest that only a narrow range (activating and deactivating) of substitutions at C-2 and C-7 are tolerated for optimal antibacterial activity and spectrum. An alkoxy (methoxy) and CN at C-2, and a halogen and hydroxyl at C-7, appeared to be preferred in this series. Substitutions on the other three carbons generally have detrimental effect on the activity. No clear hERG activity SAR emerged from these substitutions.

Structure activity relationship of C-2 ether substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-5)

“…The (Table 1) however with detrimental effect on the hERG activity (13, IC 50 0.7 lM vs 2.0 lM, 3) consistent with the higher c log D. The next best compounds were found to be the hydroxy ethyl (15) and the hydroxy propyl (16) ethers with improved c log D (2.25 and 2.64) but with diminished hERG binding and functional activity associated with diminished P. aeruginosa activity.…”

“…They did not show improvements in overall activity, spectrum and hERG profile other than compounds with an ether and a cyano group at C-2 with a halogen, hydroxy and a cyano at C-7. 15 We extended the study further and explored the ether substitution at C-2 with a fluoro substituent (one of the best substitutions for attenuation of hERG activity) at C-7 of the 1,5-napthyridine moiety. This Letter describes the synthesis and SAR of the C-2 ether substituted C-7 fluoro-1,5-naphthyridine of the oxabicyclooctane linked NBTIs.…”

“…Synthesis of the hydroxy compound (5) and key intermediate 68 (Schemes 1-3) were reported earlier. 13,15 In general 2-hydroxy-naphthyridyl intermediate 68 was alkylated with appropriately protected alkyl bromides to afford almost exclusively O-alkylated product 69 (Scheme 1). The deblocking of the Boc group by a reaction of 69 with trifluoroacetic acid provided free amine 70.…”

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

“…The molecules that inhibit hERG potassium channel lead to QT interval prolongation and sudden death. In the previous reports we have described modifications on all three structural moieties of NBTIs: left-hand side (LHS) (15,16), right-hand side (17), and linker (18). We found that maximal modulation of the hERG activity was achieved from modifications of the DNA binding motif of the left-hand-side moiety, particularly introduction of a hydroxy tricyclic group (e.g., Fig.…”

Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6)

“…14 In order to maintain Gram-negative activity and spectrum, we focused our SAR study on the both series. Recently we reported SAR around the LHS 1,5-naphthyridine 15,16 and hydroxy tricyclic 1,5-naphthyridinone, 14 as well as a survey of RHS moieties applicable to the hydroxy tricyclic series. 17 This Letter focuses on the synthesis and SAR of pyridoxazinone-substituted oxabicyclooctane linked NBTIs along with the defining an understanding of the role of the NH at position-7 of the linker.…”