학술논문
Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1Electronic supplementary information (ESI) available. See DOI: 10.1039/d0md00174k
Document Type
Article
Author
Kirk, R.; Ratcliffe, A.; Noonan, G.; Uosis-Martin, M.; Lyth, D.; Bardell-Cox, O.; Massam, J.; Schofield, P.; Hindley, S.; Jones, D. R.; Maclean, J.; Smith, A.; Savage, V.; Mohmed, S.; Charrier, C.; Salisbury, A-M.; Moyo, E.; Metzger, R.; Chalam-Judge, N.; Cheung, J.; Stokes, N. R.; Best, S.; Craighead, M.; Armer, R.; Huxley, A.
Source
MedChemComm; 2020, Vol. 11 Issue: 12 p1366-1378, 13p
Subject
Language
ISSN
20402503; 20402511
Abstract
The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 μg mL−1against fluoroquinolone-resistant Staphylococcus aureus. Although in vitrohERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.