Heteroaryliumthio substituted carbapenem derivatives: Synthesis and in vitro activity of 1β-methyl-2-(dihydropyrrolotriazoliumthio)carbapenems

Article abstract of DOI:10.7164/antibiotics.46.1866

The syntheses of five thiols, including three dihydropyrrolotriazoliumthiol salts, 1,4-dimethyl-5-mercaptomethyl-1,2,4-triazolium trifluoromethanesulfonate, and 6-mercapto-6,7-dihydro-5h-pyrazolo[1,2-a][1,2,4]triazolium chloride; and the addition of these thiols to 4-nitrobenzyl (IR,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-cm -3-carboxylate and the subsequent hydrogenolysis of the addition products is described. The latter thiol provides a new route towards the preparation of L-627 (LJC 10,627). The compounds were evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria and their antibacterial activities compared with imipenem. The compounds were measured for their hydrolytic stability to dehydropeptidase I (DHP-I) relative to imipenem. The five compounds generally had poorer Gram-positive and Pseudomonas activity than imipenem, although their Gram negative activity was variably improved. The monocyclic triazolium analog was nearly comparable in overall activity to the four bicyclic heterarylium analogs evaluated, including L-627 (LJC 10,627), All compounds were more stable to DHP-I than imipenem, although minor differences existed among them.