Synthesis of 1,4- and 2,6-diazabenzanthrones as novel antimicrobial compounds

In recognition of the antifungal activity of Sampangine (1,6-diazabenzanthrone) the preparation of other aza-analogs of benzanthrone was addressed. The syntheses of 3-phenyl-7H-naphtho [1,2,3-de][2,6]naphthyridine and 9,10-dimethyl-7H-naphtho[3,2,1-de)[1,6]naphthyridin-7-one are given. The 3-phenyl-7H-naphtho[1,2,3-de][2,6]-naphthyridine was synthesized via a linear synthesis utilizing the previously reported 1-chloro-2,6-naphthyridine as an intermediate. The optimization of the literature synthesis of this compound is given. The cyanation of 2,6-naphthyridine, which represented the first reported cyanation of this ring system, was studied and optimized under various conditions. The next synthetic step involved the Grignard reaction of this nitrogen containing heteroaromatic nitrile with phenyl magnesium bromide. Three major products, 1-benzoyl-2,6-naphthyridine, 1-benzoyl-5-phenyl-2,6-naphthyridine and 1-cyano-5-phenyl-2,6-naphthyridine, were obtained. The last synthetic step involved a peri ring closure of a diaryl ketone, known as the Scholl reaction. This represented the first account of the Scholl reaction applied to nitrogen containing heterocyclic compounds. The product of the Scholl reaction was a reduced species which supports a reductive environment of the reaction. The structures of all of the products were characterized by spectroscopic techniques. The synthesis of the 9,10-dimethyl-7H-naphtho[3,2,1- de][1,6]naphthyridin-7-one was accomplished in a overall process of eight steps starting from 2,5-dimethoxybenzaldehyde. A crucial intermediate of the synthesis was the previously reported 1,7,8-trimethylbenzo[ g]isoquinoline. It was prepared via a Diels-Alder reaction of 1-methylisoquinoline-5,8-dione with 2,3-dimethyl-1,3-butadiene. The 1,7,8-trimethylbenzo[g]isoquinoline was easily converted into the 9,10-dimethyl-7H-naphtho[3,2,1- de][1,6]naphthyridin-7-one with a satisfactory yield. This work represented the first preparation of 1 -methylisoquinoline-5,8-dione, 1,7,8-trimethylbenzo[ g]isoquinoline and 9,10-dimethyl-7H-naphtho[3,2,1- de][1,6]naphthyridin-7-one. Their structures were characterized by combination of the spectroscopic techniques. Some of the newly prepared compounds, namely 1-benzoyl-2,6-naphthyridine, 3 phenyl-7H-naphtho[1,2,3-de][2,6]naphthyridine and 9,10-dimethyl-7H-naphtho[3,2,1-de][1,6] naphthyridin-7-one, were qualitatively tested against fungi Candida albicans and Aspergillus fumigatus. All of them showed fungicidal activity against the tested organisms. The quantitative evaluation of the inhibitory effect of the 9,10-dimethyl-7H-naphtho[3,2,1- de][1,6]naphthyridin-7-one is reported. The minimum inhibitory concentration was less than 1 mug/ml which fell in the range of the well known antifungal agent Amphotericin B. Therefore the newly prepared compounds may be useful as leads in the quest of new antifungal agents.