Nalidixic acid analogues

The condensation of 4-aminopyridine (145) with diethyl ethoxymethylenemalonate (EMME) gives 3-ethoxycarbonyl-l,6-naphthyridin-4-one (146) from which compound (2) was obtained by standard procedures (50JOC1224,60JCS1790,58LA(612)153,65JHC393). A recent application of this synthesis is for the preparation of nalidixic acid analogues (147) (82CPB2399). 

Medicinally important naphthyridine derivatives such as analogues of the antibacterial agent naladixic acid (445) <91MI 715-02) have been discussed in CHEC-I <84CHEC-i(2)58i> and in another review <83AHC147>. Tosufloxacin tosylate (446) is an example of a nalidixic acid analogue. 

The greatest medicinal interest in pyridopyrimidines has been in another type of antibacterial derivative, the analogues of nalidixic acid, piromidic (68) (71CPB1426) and pipemidic (69) acids (75JMC74). 

Other studies have dealt with hydrogen abstraction from the solvent by the photosensitizing drug nalidixic acid [98a], hydrogen transfer in an-thraquinone/xanthene systems [98b], photoreductions of quinones by alcohols [98c] and of acetylenic ketones by various hydrogen donors [98d], the oxidation of NADH analogues [98e-98g], and the reaction of 4-methyl-2-quinolinecarbonitrile with optically active phenylpropionic acid [98h],... 

Fluoroquinolones designate distinctly an improvement of the earlier structural analogues, such as cinoxacin, nalidixic acid, oxolinic acid, and pipemidic acid, for being relatively much more potent in vitro. Besides, the fluoroquinolones do exhibit a definitely broader antibacterial spectrnm, the essentially consist of both Gram-positive and Gram-negative microorganisms. 

Since the introduction in 1963 of nalidixic acid (Table I), l-ethyl-1,4-dihydro-7-methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, as a systemic Gram-negative antibacterial agent, a large number of analogues have been synthesized and evaluated, some of which have come onto the international market. CL2) A comprehensive review has outlined the synthetic methods, microbiology and structure activity relationships of those derivatives reported prior to 1977.(2)... 

Nalidixic acid and its analogues act by inhibition of bacterial DNA synthesis by inhibiting a bacterial DNA gyrase classified as a type II topoisomerase.(7.8.9.10) Resistance and cross resistance are seen with nalidixic acid and the fluoroquinolones. It seems to be related to decreased cellular permeability and has been considered plasmid independent. ( ,5,11,12) More recently, reports have appeared of genes carrying the resistance traits normally found on plasmids. (13,1 )... 

Nalidixic acid is indicated for the treatment of urinary tract infections. The success of nalidixic acid in the 1960s led to the synthesis of other analogues of comparable activity such as cinoxacin and acrosoxacin. Information gleaned from the activity of several synthesised quinolones indicates that the following stractural requirements are essential for activity ... 

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