Nalidix acid

The antibacterial agent nalidixic acid [389-08-2] (37) is formed by reaction of 2-ainino-6-methylpyridine [1824-81 -3] with an alkoxymethylenemalonic ester to form the 1,8-naphthyridine carboxyUc ester followed by alkylation and ester hydrolysis (37). 

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). 

Derivatives of nalidixic acid (69a-69d), containing an amino or acetyl-amino substituent at position 7 and an alkyl group at N-1, were successfully nitrated to give (70a-70d). However, in all cases hydrolysis of the amino and acetylamino group was observed (79YZ155 80CPB235). 

Treatment of ethyl 4-chloro-7-diethylamino-6-nitro-l,8-naphthyridine 3-carboxylate (104) with the amines RH [R = N(CH2)s NH(CH2)N(C2Hs)2] gives the corresponding 4-amino derivatives [105, R = N(CH2)s, 74% and 105, R = NH(CH2)N(C2Hs)2, 50%]. With diethylamine the 7-chloro-6-nitro derivative of nalidixic acid (i.e., 106) yields the 7-diethylamino compound 107 (62%) (79YZ155). 

Anti-mycobacterium avium activity in vitro of 3-carboxy-7-methyl-6-nitro-l-ethyl-l,8-naphthyridin-4(lH)-one (6-nitro derivative of nalidixic acid) was demonstrated (93MI1). 

Because of the number of citations, only selected imidazoquinolines are described, and biological activity is mentioned only briefly. The largest increase in the number of citations was caused by the discovery of the antibacterial properties of nalidixic acid type drugs. Efforts to prepare the bioisosters, for example of oxolinic acid, intensified in the early 1970s, and the discovery of the carcinogenic properties of 2-aminoimidazoquinolines followed in the early 1980s. These azoloquinolines can be considered as benzene-separated deazapurines. 

A 1,8-naphthyridine, nalidixic acid (39), shows clinically useful antibacterial activity against Gram-negative bacteria as such, the drug is used in the treatment of infections of the urinary tract. Condensation of ethoxymethylenemalonate with 2-amino-6-methylpyridine (36) proceeds directly to the naphthyri-dine (38) the first step in this transformation probably involves an addition-elimination reaction to afford the intermediate, 37. W-Ethylation with ethyl iodide and base followed by saponification then affords nalidixic acid (39). 

Ethoxymethyleneethyl malonate Floctafenine Nalidixic acid Pipemidic acid Piromidic acid Rosoxacin... 

Gallamine triethiodide Ibuprofen Nalidixic acid Oxetorone fumarate Oxolinic acid Piroheptine Rosoxacin Tridihexethyl iodide Ethyl 4-iodobutyrate Meptazinol... 

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