Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors

• Published in: Journal of medicinal chemistry Vol. 58; no. 21; pp. 8503 - 8512
• Main Authors: Zhang, Jing, Yang, Qingyi, Cross, Jason B, Romero, Jan Antoinette C, Poutsiaka, Katherine M, Epie, Felix, Bevan, Douglas, Wang, Bin, Zhang, Yanzhi, Chavan, Ajit, Zhang, Xin, Moy, Terence, Daniel, Anu, Nguyen, Kien, Chamberlain, Brian, Carter, Nicole, Shotwell, Joseph, Silverman, Jared, Metcalf, Chester A, Ryan, Dominic, Lippa, Blaise, Dolle, Roland E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.11.2015; Amer Chemical Soc
• Subjects: Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Chemistry, Medicinal; Crystallography, X-Ray; DNA Gyrase - metabolism; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - enzymology; Gram-Positive Bacterial Infections - drug therapy; Gram-Positive Bacterial Infections - microbiology; Humans; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - enzymology; Models, Molecular; Pharmacology & Pharmacy; Science & Technology; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Urea - analogs & derivatives; Urea - pharmacology; DNA GYRASE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00961

The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.