Studies on prodrugs. 5. Synthesis and antimicrobial activity of N-(oxoalkyl)norfloxacin derivatives

Abstract

Several N-(oxoalkyl)norfloxacin derivatives (3a-g) were synthesized and evaluated for antibacterial activity in vitro and in vivo. Most of the compounds exhibited in vitro activity comparable to that of norfloxacin for Gram-positive bacteria, whereas their activity was lower than for Gram-negative bacteria. N-(2-Oxopropyl)norfloxacin (3b) liberated norfloxacin in the blood after oral administration in mice, and the serum level of norfloxacin was about 3-fold higher than that of norfloxacin itself. Thus, 3b showed high antibacterial activity in vivo.

Synthesis and biological evaluation of novel β-hydroxy benzimidazolyl sulfone fluoroquinolones by selective oxidation using ammonium molybdate catalysed H2O2

“…Initially (3S)-9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H- [1,4]oxazino[2,3, 4-ij]quinoline-6-carboxylic acid, 1, on reaction with piperizine in presence of triethylamine in acetonitrile under reflux given the previously reported [21] (S)-9-fluoro-3,7-dihydro-3-methyl-7-oxo-10-(piperazin-1-yl)-2H- [1,4]oxazino [2,3,4-ij] quinoline-6-carboxylic acid 2 on treatment with epichlrohydrine in presence of NaOH in acetone at 40-45 °C gave the corresponding 9-fluoro-3,7-dihydro-3-methyl-10-(4-((oxiran-2-yl)methyl)piperazin-1-yl)-7-oxo-2H- [1,4]oxazino [2,3,4-ij] quinoline-6-carboxylic acid, 3, as shown in Scheme 1.…”

“…The board spectrum of antibiotic activity of these compounds is mainly due to the presence of a fluorine atom at position C-6, chemical modification at position C-7 (piperazine moiety) of fluroquinolones ring system [3][4][5][6]. Literature survey and Structure activity relationship (SAR) analysis reveals that the substitution/modifications at C-7 position of fluroquinolones nucleus lead to the synthesis of new and improved fluoroquinolones antibacterials [7,8] with enhanced activity similar to antibiotics like levofloxacin, moxifloxacin, ciprofloxacin, ofloxacin and enrofloxacin ( Figure 1).…”

Synthesis and antibacterial activity of N-[2-(5-bromothiophen-2-yl)-2-oxoethyl] and N-[(2-5-bromothiophen-2-yl)-2-oximinoethyl] derivatives of piperazinyl quinolones

“…11 Accordingly, a number of quinolones 4 with a 2-oxoethyl or 2-oximinoethyl derivative attached to the piperazine ring at C-7 position were synthesized and evaluated for antibacterial activity by us and others. [12][13][14][15][16][17][18][19] In continuation of our efforts to complete the SARs of N-piperazinyl quinolones and to achieve a better antimicrobial profile at lower concentrations against Grampositive bacteria, herein, we report the synthesis and antibacterial activity of a new series of N-piperazinyl quinolones (5, 6 and 7) containing 2-(5-bromothiophen-2-yl)-2-oxoethyl or 2-(5-bromothiophen-2-yl)-2-oximinoethyl groups (Fig. 2).…”

In vivo evaluation of NM441, a new thiazeto-quinoline derivative

“…In the course of our search for a new 6-fluoroquinolone antibacterial agent, thiazeto-quinoline carboxylic acid derivatives with a sulfur atom at the C-2 position were tested, and a new compound, NM394, 6-fluoro-1-methyl-7-(1-piperazinyl)-4-oxo-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, was chosen as the most promising compound with potent antibacterial activity in vitro (7). However, despite its broad spectrum of activity, the protective effect ofNM394 against experimental infections is poor when it is administered orally.…”

“…However, despite its broad spectrum of activity, the protective effect ofNM394 against experimental infections is poor when it is administered orally. In order to increase the absorption of NM394 from the intestinal tract, the prodrug of NM394, NM441, 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo -1,3 -dioxolen -4 -yl)methyl-1 -piperazinyl] -4 -oxo-4H- [1,3]thiazeto [3,2-a]quinoline-3-carboxylic acid, was synthesized ( Fig. 1).…”