A Novel Antibacterial 8-Chloroquinolone with a Distorted Orientation of the N1-(5-Amino-2,4-difluorophenyl) Group

Abstract

Fluoroquinolones represent a major class of antibacterial agents with great therapeutic potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria. This compound is significantly more potent than trovafloxacin against clinical isolates: 30 times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphylococcus aureus. The structure-activity relationship (SAR) study revealed that a limited combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom (or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8 Cl atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its analogues demonstrated that a highly distorted orientation was induced by a steric hindrance of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained conformation should be a key factor for the potent antibacterial activity.

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

“…This easy decarboxylation outcome of 22a-c can be explained in terms of fairly strong electron-withdrawing effect of the heterocyclic N1 moiety. Although we attempted the nucleophilic substitution reactions of 22a-c without decarboxylation by derivatizing to their boron difluoride intermediates or by the method in the presence of LiCl, 15) desirable products 25a-c have never been obtained. On the other hand, treatment of 21a-c with 3-(4-methoxyanilino)azetidine (10b) at room temperature or 40°C in MeCN afforded 7-azetidinylquinolone ethyl esters 24a-c in 56-78% yields.…”

“…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.…”

Morita.Baylis.Hillman Route to 8,9,9a,10-Tetrahydrobenzo[b][1,8]naphthyridine-6(7H)-ones and 3,4,4a,5-Tetrahydrodibenzo[b,g][1,8]naphthyridine-1(2H)-ones

“…1 1,8-Naphthyridine derivatives show a broad range of interesting physiological activities such as antiinflammatory, 2,3 analgesic, 2 antiaggressive, 3 anticancer, 4 antibacterial, 5 antitumor, 6 antihypertensive, 7 antiallergitic, 8 and antimalarial. 9 Several synthetic approaches have been developed to form the 1,8-naphthyridine derivatives, 10 but due to their great importance, the development of new synthetic methods remain an active research area.…”