Fluoronaphthyridines and quinolones as antibacterial agents. 1. Synthesis and structure-activity relationship of new 1-substituted derivatives

Abstract

A series of novel 7-piperazinyl-1-substituted-6-fluoroquinolones and naphthyridines have been prepared and their antibacterial activities evaluated. These derivatives are characterized by having alkyl, alkenyl, arylalkyl, cycloalkyl, and cycloalkenyl groups at the 1-position. As a result of this study, derivatives 7 and 26, which are substituted with tert-butyl groups at N-1, were found to possess excellent in vitro and in vivo potency, particularly against Staphylococcus aureus, comparable to that of norfloxacin or ciprofloxacin. Structure-activity relationships of N-1 substituted alkyls and cycloalkyls are also discussed.

Synthesis of new aryl substituted 5-alkylidene-2(5H)-furanones

“…Multiplicities are recorded as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) and combinations of these. 13 C NMR spectra were recorded with a Bruker DPX300 spectrometer (75 MHz) and chemical shifts are reported in ppm internally referenced to solvent nuclei (δ), and identifiable carbons are given. Ultraviolet spectra were measured on a Cary 100 spectrophotometer and data are reported as wavelength (λ) in nm and absorption coefficient (ε) in M (E)-6-Methyl-4-oxohept-2-enoic acid (6a).…”

“…8,10 Synthetic fimbrolide 2 (R = Br) was found to reduce P. aeruginosa levels in the lungs by three orders of magnitude in a pulmonary mouse model. 9 Intrigued by the exocyclic iso-propyl moiety in the structurally related natural product pulchellalactam 12 3 as well as the presence of the similar tert-butyl group in various antibacterial compounds, 13,14 we set out to synthesize brominated furanones 4 (R 1 or R 2 = Br) carrying a vinylic iso-propyl or tert-butyl substituent at the C5 position ( Figure 2). Compounds where the C4-bromine was switched to the C3 position were also targeted to afford a more comprehensive library of furanones for structure-function investigations.…”

The Chemical and Biological Aspects of Fluoroquinolones Reality and Dreams

“…(6.1) which could synthesize many other quinolones bearing a large variety of N-1 substituents e.g. enrofloxacin [19,61], N-1 methyl, ethanyl analogs [60].…”

“…Following this idea of bifunctionality, a dual action penem with a putative dual mode of action was synthesized by Ettore Perrone et al [32] named as carbamate linked and ether linked quinolonyl penems (60). These penems confirm the bifunctional activity i.e.…”

1,8-Naphthyridines II: synthesis of novel polyfunctionally substituted 1,8-naphthyridinones and their degradation to 6-aminopyridones

“…The most common method for the synthesis of 1,8-naphthyridine-4-ones begins with condensation of ethyl 2-chloronicotinoylacetates I with either triethylorthoformate/acetic anhydride, dimethylamine dimethylacetal, or an iminochlorothioformate, followed by the reaction of intermediates II with amine to give the corresponding enamino ketoesters III. Subsequent intramolecular cyclization, under basic conditions, leads to 1,8-naphthyridone derivatives IV [25][26][27][28][29][30][31] (Chart 1). We have previously explored a new synthetic approach for the synthesis of polyfunctionally substituted 1,8-naphthyridin-2-one derivatives [32], and describe herein a new, efficient and convenient procedure for the synthesis of hitherto unreported polyfunctionally substituted 1,8-naphthyridin-2-one, 1,8-naphthyridin-2,7-dione.…”