7-Azetidinylquinolones as antibacterial agents. Synthesis and structure-activity relationships

Abstract

A series of novel antibacterial quinolones and naphthyridones has been prepared which contain 7-azetidinyl substituents in place of the usual piperazine or aminopyrrolidine groups. These azetidinyl derivatives were evaluated for in vitro activity by determining minimum inhibitory concentrations against a variety of bacteria. In vivo efficacy in the mouse infection model and blood levels in the mouse were determined for several compounds. The influence on the structure-activity relationships of varying substituents in the azetidine ring and at position 8 (CH, CF, CCl, N) and N-1 (ethyl, fluoroethyl, cyclopropyl, tert-butyl, 4-fluorophenyl, and 2,4-difluorophenyl) was also studied. Compounds with outstandingly broad-spectrum activity, particularly against Gram-positive organisms, improved in vivo efficacy, and high blood levels were identified in this work. 7-Azetidinyl-8-chloroquinolones were considered as warranting further development.

Synthesis of New Quinolone Antibiotics Utilizing Azetidine Derivatives Obtained from 1-Azabicyclo[1.1.0]butane

“…Since the desirable reaction did not proceed under the same conditions as described in Table 3, we focused on N-benzyl-3-bromoazetidine (13) 8) which can be exploited to synthesize various azetidine derivatives via suitable nucleophilic substitution reaction. The compound 13 was obtained via two steps of reactions involving the ringopening reaction of ABB (3) with HBr to give 3-bromoazetidine hydrobromide (12) followed by benzyl protection of the N1 group, but this reaction procedure resulted in a low yield (24% total yield). We carefully examined the reaction conditions to obtain 13 from ABB (3) by one step of reaction.…”

“…Although several examples of 7-azetidinylquinolones have been reported, [12][13][14][15] there have been not many prominent quinolone antibiotics bearing the azetidinyl substituent groups thus far. We envisaged that the introduction of azetidine derivatives onto the C7 position of the quinolone nucleus might enhance their antibacterial activities against MRSA.…”

“…These azetidine moieties have often been found in many natural products 11) and biologically active compounds such as carbapenems 1) and new quinolone antibiotics. [12][13][14][15] 1,3,3-Trinitroazetidine (TNAZ), 16,17) an insensitive high explosive, was also synthesized by using ABB (3). In recent years, we established an efficient method for synthesis of ABB (3) starting from allylamine (1) via 2,3-dibromopropylamine hydrobromide (2), and reported its application to the synthesis of several azetidine derivatives, as shown in Chart 1.…”

“…10) We now describe, in detail, a convenient method of synthesizing several 3-sulfenyl-and 3-aminoazetidine derivatives utilizing ABB (3), and we discuss the synthesis and antibacterial activities of new quinolone antibiotics incorporating these azetidine derivatives to the C7 position. Although several examples of 7-azetidinylquinolones have been reported, [12][13][14][15] there have been not many prominent quinolone antibiotics bearing the azetidinyl substituent groups thus far. We envisaged that the introduction of azetidine derivatives onto the C7 position of the quinolone nucleus might enhance their antibacterial activities against MRSA.…”

1,8‐Naphthyridine Derivatives: A Review of Multiple Biological Activities

“…Compounds were also tested for inhibition of supercoiling activity of DNA gyrase from M. smegmatis. The shortlisted active compound, 1-tert-butyl-1,4-dihydro-7-(4,4-dimethyloxazolidin-3-yl)-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (54), demonstrated potential in vitro activity against MTB and MDR-TB (3 and 455 times more potent than isoniazid against MTB and MDR-TB, respectively). This compound also showed remarkable in vivo activity in animal model by decreasing the bacterial load in lung and spleen tissues.…”