Synthesis and Antibacterial Activity of Novel Cephalosporins Containing 2,3-Disubstituted-1,8-naphthyridiniummethyl Group at the C-3 Position

Abstract

Nowadays, researches for development of β-lactam antibiotics have been done extensively for a long time. Above all, cephalosporins, widely used antibiotics for the treatment of infections, have been studied actively and modified chemically because of the continuing need to produce more effective therapy. In recent years, a number of cephalosporins containing a quaternary ammoniummethyl group at the C-3 position and a 7β-[(Z)-2-(2-aminothiazole-4-yl)-2-alkoxyiminoacetamido] group at the C-7 position such as cefpirome (CPR), ceftazidime (CAZ) and cefepime (CEPM) have been prepared. They have shown excellent activities against Gram-positive bacteria including Staphylococcus aureus and also Gramnegative bacteria including Pseudomonas aeruginosa. In the previous paper, we were interested in subsititution at the C-3 position by 2,3-disubsitituted-1,8-naphthyridine derivatives. So we have synthesized various new cephalosporins having the aminothiazoylmethoxyimino moiety at the C-7 position and 1,8-naphthyridinium moiety at the C-3 position of the cephem nucleus. Among them, the product 3a, having a 2-amino-1,8-naphthyridine-3-carboxamide 1 at the C-3 position, has the best activity against most bacteria (Figure 1). Therefore, our effort to expand the antibacterial potency has been made toward a chemical modification of product 3a by various alkyl groups and carboxylic groups at the C-7 oxyimino moiety. The C-3 substituent, 2-amino-1,8-naphthyridine-3-carboxamide 1, was made from 2-aminonicotinaldehyde with cyanoacetamide using piperidine as catalyst by Friedlander reactions. The quaternary ammonium cephalosporins, 3a-3f, were synthesized according to the general procedure as shown in Scheme 1. The silylation of 7β-[(Z)-2-(2-aminothiazole-4yl)-2-alkoxyiminoacetamido]-3-cephem-4-carboxylic acid, 2a-2f, was carried out with N-methyl-N-(trimethylsilyl)-