ABSTRACT
According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.
Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Gyrase/metabolism , Drug Design , Drug Resistance, Multiple, Bacterial/drug effects , Gram-Positive Bacteria/drug effects , Topoisomerase II Inhibitors/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Gram-Positive Bacteria/metabolism , Hep G2 Cells , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistryABSTRACT
There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.
Subject(s)
Anti-Bacterial Agents/chemistry , DNA Topoisomerases, Type II/metabolism , Thiazoles/chemistry , Thiazolidines/chemistry , Topoisomerase II Inhibitors/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cell Survival/drug effects , DNA Topoisomerases, Type II/chemistry , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial/drug effects , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli/isolation & purification , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hep G2 Cells , Humans , Microbial Sensitivity Tests , Mutation , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacologyABSTRACT
An iron(III)-catalyzed method for the rapid and highly regioselective iodination of arenes has been developed. Use of the powerful Lewis acid, iron(III) triflimide, generated in situ from iron(III) chloride and a readily available triflimide-based ionic liquid allowed activation of N-iodosuccinimide (NIS) and efficient iodination under mild conditions of a wide range of substrates including biologically active compounds and molecular imaging agents.
