Novel Benzothiazole-urea Hybrids: Design,Synthesis And Biological Activity As Potent Anti-Bacterial Agents Against MRSA

Staphylococcus aureus is a Gram-positive opportunistic pathogen with a diameter of 0.5-1.5μm and irregularly arranged grape clusters,and is one of the most common pathogens in hospital and community settings.Since the first discovery of methicillin-resistant Staphylococcus aureus（MRSA）infection in 1960,new mutant strains have emerged at a rate far outpacing the development of antibacterial drugs.MRSA infection has become one of the public health problems of the 21st century.Novel benzothiazole-urea hybrids were designed,synthesized and evaluated their anti-bacterial activity.They only exhibited anti-bacterial activity against Gram-positive bacteria,including methicillin-resistant S.aureus（MRSA）,amongst them,compounds 5f,5i,8e,8k and 8l exhibited potent activity（MIC=0.39 and 0.39/0.78μM against SA and MRSA,respectively）.SAR showed:（i）the linker between benzothiazole and urea was key to the activity;（ii）4-CF₃ or 3,4-di F of phenylurea increased the activity.Compounds 8e and 8l not only inhibited the formation of biofilms but also eradicated preformed biofilms.Compound 8l had membrane disruption,little propensity to induce resistance,benign safety and in vivo anti-MRSA efficacy superior to vancomycin in a mouse model of abdominal infection.Therefore,our data demonstrated the potential to advance benzothiazole-urea hybrids as a new class of antibiotics.