Synthesis and in Vitro Activity towards Mycobacterium Tuberculosis of L-serinyl Ester and Amino Derivatives of Pyrazinoic Acid

Abstract

Reactions between either L-serine methyl ester hydrochloride (1), or the cbz derivative, methyl (S)-(+)-2-(benzyloxycarbonylamino)-3-hydroxypropanoate (2), and pyrazinoyl chloride (3), have been studied. Methyl (S)-(+)-2-benzyloxycarbonylamino-3-[(pyrazinecarbonyl)oxy]propionate (4), methyl (S)-(+)-3-hydroxy-2-[(pyrazine-2-carbonyl) amino]propionoate (7), methyl 2-[(pyrazinecarbonyl)amino]acrylate (8) were obtained. Additional products, methyl (S)-(+)-2-benzyloxycarbonylamino-3-formyloxypropionoate (5) and methyl (R)-(+)-2-benzyloxycarbonylamino-3-chloropropionoate (6), were isolated from reaction of 2 with 3, in the presence of DMF remaining from the preparation of 3, from pyrazinecarboxylic acid. The coupling of pyrazinecarboxylic acid with 1, in the presence of DCC was prevented by the formation of the unreactive adduct between DCC and pyrazinoic acid. The compounds were tested against M. tuberculosis: compounds (8) and (6) exhibited a MIC (μg/ml) value of 50 and 100, respectively, compared to the MIC value of 100 for the first line TB drug, pyrazinamide. The confirmation of the structure of (8) was obtained via X-ray crystallography.