Quinolone antimicrobial agents: structure-activity relationships

The rapid growth in the quinolone research changed the whole face of the previous SAR concepts. So far structural modifications at all positions of the quinolone nucleus except the 4-oxo group have successfully lead to the discovery of potent antimicrobial agents. At position 1, ethyl and its bioisosteres such as fluoroethyl, methylamino, methoxy, etc, are optimal substituents while some groups with a tert.-carbon atom directly connected with N-1 position such as tert.-butyl, phenyl, etc. are also promising for the activity of the quinolone compounds. Steric bulk is no longer considered as the only factor which influences the activity of the compounds. However, it could only be answered by further research how big such steric bulk tolerance at position 1 would be and what is the precise role that the N-1 substituents play in the mechanism of action of the quinolones. Fluorination has been extensively employed as a modifying technique to almost all possible positions of the quinolone nucleus. While being maintained at C-6, a fluorine atom was also introduced to C-5 and C-8 to produce potent analogues. Fluorination of N-1 substituents, e.g., fluoroethyl, fluorophenyl, etc., and C-7 substituents, e.g. 2-((fluoromethyl)piperazinyl and fluorohomopiperazinyl, etc., yielded also a handful of potent quinolones. Amino-and chloro groups are found to be beneficial for positions 5 and 8, respectively. The "medium size" concept concerning the 7-substituents is no longer valid. Numerous potent quinolones with a "large" group substituted on position 7 have been discovered. A certain amount of free rotation in the 7-substituents appears to emerge as an important factor which influences the activity of the compounds. Some radical modifications in 7-substituents, e.g. C--C linkage between the nucleus and 7-substituents, afforded new insight into the SAR of quinolones. A planarity between the 4-oxo group and 3-carboxylic group may be important for binding to the DNA gyrase as demonstrated by a group of enolized isothiazoloquinolone derivatives. Further research will surely lead to the better understanding on the mechanism of action of quinolones as well as the discovery of analogues with better activity features, lower adverse effects and more favourable pharmacokinetic properties.