Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids

Abstract

A series of [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids and their esters were prepared and evaluated for antibacterial activity. The derivatives with a hydrogen or methyl group at C-1, fluorine at C-6, and piperazinyl or 4-methyl-1-piperazinyl group at C-7 showed superior in vitro antibacterial activity, and the derivatives with 4-methyl-1-piperazinyl group at C-7 had potent in vivo activity. Compound 29a (NM394) showed excellent in vitro antibacterial activity and low toxicity but poor absorption from the gastrointestinal tract. Compound 29ee (NM441), an N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] derivative of 29a, was found to possess a favorable pharmacokinetic profile and oral activity superior to that of ciprofloxacin in experimental animals.

In vivo Antibacterial Activity of a Prodrug of NM394, a Thiazetoquinoline Carboxylic Acid Derivative

“…NM394 is the first thiazetoquinoline carboxylic acid derivative reported to have potent antibacterial activity [4,5], but we have found it to be poorly absorbed when orally administered. As we thought that the low bioavailability of NM394 was due to its high hydrophilicity (log p = -0.86), we have synthesized 37 derivatives which includes lipophilic prodrug moieties in order to improve the absorption of NM394 from the intestinal tract.…”

“…However, we have studied quinolone derivatives with a bridge connecting the N-1 and C-2 positions in the expectation that the resulting tricyclic structure would retain antibacterial activity. We have found that such thiazolo-and thiazetoquinoline carboxylic acid derivatives have potent in vitro antibacterial activity [4,5]. Among the derivatives tested, 1 (NM394), 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ( fig.…”

4‐Quinolone Derivatives and Their Activities Against Gram‐negative Pathogens

“…), and the thiazetoquinolone prulifloxacin that exhibited excellent potency against Gram‐negative pathogens belongs to this kind of 4‐quinolones . Based on that, various [1,3]thiazeto[3,2‐ a ]quinolone 6 were examined for their antibacterial activities, and the SAR revealed that the size of the substituents at thiazeto ring (R 1 position) influenced the activity greatly, and in general, the relative order was –H ≥ –Me > –Et > unsubstituted/substituted phenyl groups . Some of them were comparable with OLFX and CPFX in both in vitro and in vivo tests, so this kind of derivatives has the potential to develop novel antibacterials.…”

Antimycobacterial and phototoxic evaluation of novel 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid

“…However, no large systematic study has been undertaken either to optimise the fused quinolone antibacterials against MTB or to examine the specific structure-activity relationship of the fused quinolone against MTB. Segawa et al [5] reported antibacterial potency of tricyclic 7-substituted-6-halo-4-oxo-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids, which showed excellent in vitro antibacterial activity. Herein we report the antimycobacterial results of newer thiazeto [3,2-a]quinolone derivatives modified at the sixth and seventh position with fluoro/nitro groups and various unreported bulky secondary amines, respectively.…”