Synthesis of antimicrobial agents. V. Synthesis and antimicrobial activities of some heterocyclic condensed 1,8-naphtyridine derivatives.

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Abstract
To search for compounds with higher activity than thiazolo[5,4-b], imidazo-[4,5-b] and triazolo[4,5-b][1,8]naphthyridine derivatives against Pseudomonas aeruginosa, some heterocyclic condensed 1,8-naphthyridine derivatives were synthesized by using bifunctional 6,7-disubstituted 1,8-naphthyridine as a starting material. Thiadiazolo[5,4-b] and oxazolo[5,4-b][1,8]naphthyridine derivatives (3) and (5) were prepared by hydrolysis of the 6-amino-7-chloro-3-ester (1) with sodium hydroxide or sodium hydrosulfide, followed by cyclization with acetic anhydride or sodium nitrite. Pyrazolo[3,4-b] and isothiazolo[5,4-b][1,8]naphthyridine derivatives (12) and (14) were synthesized by ring cyclization of the 7-chloro-6-formyl-3-ester (10) with methyl hydrazine or ethanolic ammonia in the presence of S, followed by hydrolysis. Thieno and furo [2,3-b][1,8]naphthyridine derivatives (20) and (31) were prepared through a series of reaction steps, e.g., diazotization, reduction of the nitrile ester (7) or (24), ring cyclization by ethyl mercaptoacetate or ethyl bromomalonate, hydrolysis and decarboxylation. The compounds obtained were tested for antimicrobial activities in vitro. 8-Ethyl-5,8-dihydro-5-oxothieno[2,3-b][1,8]naphthyridine-6-carboxylic acid (20) exhibited the highest activities among these compounds against many gram-negative bacteria, including P. aeruginosa, and against gram-positve bacteria.