Structure-activity relationship study of novel iminothiadiazolo-pyrimidinone antimicrobial agents

An iminothiadiazolo-pyrimidinone derivative, 0002-04-KK, harboring a furan moiety, acts as an antimicrobial agent with a minimum inhibitory concentration (MIC) against Staphylococcus aureus of 25 mu g ml(-1). Several derivatives of 0002-04-KK were synthesized and among them 0026-59-KK, harboring a nitrofuran moiety, had the most potent antimicrobial activity with an MIC of 6 mu g ml(-1). Both 0002-04-KK and 0026-59-KK inhibited the biosynthesis of DNA, RNA and proteins. Peptidoglycan biosynthesis was inhibited by 0026-59-KK, and slightly inhibited by 0002-04-KK. Derivative 0002-04-KK showed bactericidal activity in contrast to the bacteriostatic activity of 0002-04-KK. Derivative 0002-04-KK had less toxicity in silkworms (lethal dose fifty (LD50): >230 mu g g(-1)) than 0002-04-KK (LD50: 100 mu g g(-1)). The bactericidal activity against S. aureus was because of the nitrofuran moiety. These findings suggest that iminothiadiazolo-pyrimidinone compounds could be used as lead molecules to develop antimicrobial agents.