An excellent summary of structure-activity relationships by Tillotson .. or even an fused ring (for example, ofloxacin, levofloxacin both have a. Quinolone SAR • CID (Suppl 3) • S tinued useful future for .. or even an fused ring (for example, ofloxacin, levofloxacin both have a benzoxazine . The first approach to understand SAR for fluoroquinolones to kill non-growing bacteria was to coli DM moxifloxacin, levofloxacin, and gatifloxacin ; .
In vitro activity of difloxacin hydrochloride AA, and cefixime CL ,; FK against selected genital pathogens. In vitro activity of Roa new fluorinated 4-quinolone.
Synthesis and structure-activity relationships of novel arylfluoroquinolone antibacterial agents. Synthesis and biological activity of benzothiazolo[3,2-a]quinolone antibacterial agents. Enantiomers of 1-ethyl[3-[ ethylamino methyl]pyrrolidinyl]-6,8-difluoro-1,4- dihydrooxoquinoline-carboxylic acid: New structure-activity relationships of the quinolone antibacterials using the target enzyme.
The development and application of a DNA gyrase assay. New quantitative structure-activity relationships at N1 for the quinolone antibacterials. A new synthesis of 7H-pyrido[1,2,3-de][1,4]benzoxazine derivatives including an antibacterial agent, ofloxacin.
Study of Antimicrobial Quinolones and Structure Activity Relationship of Anti-Tubercular Compounds
Chem Pharm Bull Tokyo Oct;34 Geneva, Switzerland, July In-vitro and in-vivo potency of five new fluoroquinolones against anaerobic bacteria. Activity of E, a new fluoroquinolone, in vitro and in experimental cystitis and pyelonephritis in rats. Monocyclic and tricyclic analogs of quinolones: Synthesis, absolute configuration, and antibacterial activity of 6,7-dihydro-5,8-dimethylfluorooxo-1H,5H- benzo[ij]quinolizinecarboxylic acid.
Difloxacin metabolism and pharmacokinetics in humans after single oral doses. Comparative antibacterial activities of temafloxacin hydrochloride A and two reference fluoroquinolones. Isolation and characterization of norfloxacin-resistant mutants of Escherichia coli K Mutations producing resistance to norfloxacin in Pseudomonas aeruginosa.
Genetic and biochemical characterization of norfloxacin resistance in Escherichia coli. Recent advances in pharmaceutical chemistry.
J Clin Hosp Pharm. Figure 1 View large Download slide Structure of the quinolone molecule, using the accepted numbering scheme for positions on the molecule. An R indicates possible sites for structural modification.
Molecules at positions marked by a dashed box can also be changed; however, the most commonly used structure is shown here. This position is part of the enzyme-DNA binding complex, and has a hydrophobic interaction with the major grove of DNA [ 38 ]. A cyclopropyl substituent is now considered the most potent modification here, followed by addition of a 2,4-difluorophenyl [ 39 ]. Most other substituents, including one with only the wrong stearic position R -ofloxacin can presumably lower the number of molecules capable of binding to the enzyme-DNA pocket, and therefore reduce potency [ 40 ].
Interestingly, ofloxacin has a tricyclic ring structure with a CH3 attached to the asymmetric C-3 position on the oxazine ring, thus connecting positions 1 and 8 with a fused ring. Although this has been a useful alternative to the cyclopropyl substituent, the S- isomer exhibits twice the order of magnitude of activity as the R- isomer, which seems to determined by the number of molecules that can be assembled, or stacked, in the enzyme-DNA complex binding pocket [ 40 ].
Even the potency of the purified S- isomer fused ring is less than that of the cyclopropyl substituent, suggesting the difficulty of improving upon this latter modification.
This location is very close to the site for DNA gyrase or topoisomerase IV binding so it is believed that any added bulk inhibits access and results in a lower level of microbiological activity [ 739 ]. Only a sulfur, incorporated into a small ring, has been able to replace hydrogen at the R-2 position [ 39 ]. To accomplish this, researchers reconfigured positions 3 and 4. Positions 3 and 4. These two positions on the quinolone nucleus are considered critical for binding to cleaved or perturbed DNA, and no useful substitutions have yet been reported.
Therefore, the 3-carboxylate and 4-carbonyl groups are considered essential for antimicrobial activity [ 7 ]. This is a new addition to the quinolone class, in which nitrogen replaces the carbon between ring carbons C-4 and C-5 [ 41 ].
Making this alteration renumbers the other positions so that 5- becomes 6- 6- becomes 7- 7- becomes 8- and 8- becomes position 9. This substitution enhances the in vitro and in vivo mouse protection activity against gram-positive cocci, including methicillin-resistant S.
The remainder of the optimal substitutions for the oxoquinolizine derivatives are similar to those for the C-6 fluorinated agents, namely a cyclopropyl at R-1, a methyl or methoxy at R-8 R-9 oxoquinolizineand a 5- or 6-membered ring at R-7 R-8 oxoquinolizine. For the compounds studied in this report, a 5-membered ring at this position appeared slightly more active.
Interestingly, of these 2 additions to the ring substituent, the amino group gave the best in vivo activity. Bicyclic substituents at this position R-7 also appear as important approaches to enhance activity against either gram-positive or gram-negative pathogens [ 41 ]. Substituents at this position of the basic quinolone nucleus appear to have the capacity to alter overall stearic configuration planar structure of the molecule, which is how changes here are thought to affect activity [ 38 ].
Modestly sized additions, such as an amino, hydroxyl, or methyl group can markedly increase in vitro activity against gram-positive bacteria [ 3942 ], as well as enhance potency against Toxoplasma gondii [ 43 ]. Yoshida and coworkers [ 42 ] found that the methyl group enhances action against gram-positive but not against gram-negative bacteria. Halide and methoxy substituents tend to diminish activity, indicating the precise nature of the required structural modification [ 42 ]. However, for currently unknown reasons, the in vitro bacterial affects of changes made at this position are not always mirrored by an enhancement to in vivo activity when tested in an animal model [ 39 ].
The addition of a fluorine molecule here markedly improved antimicrobial activity compared to the original quinolone agents, and gave rise to the now widely used and clinically successful fluoroquinolone compounds.
Structure-activity relationships of the fluoroquinolones.
New 6-H-quinolones are currently under development that appear very promising [ 44 ]. Whatever structure is placed at this site, the substituents at positions 1, 7, and 8 continue to be key determinants of overall biological activity in the compounds under active development.
Another group of agents with novel substituents here are the 6-amino, 8-methyl quinolones, which have expanded activity against gram-positive cocci [ 45 ]. A tetrahydroisoquinoline substituent at C-7 seems to be a most useful addition for the 6-amino agents, increasing in vitro activity anywhere from 4-fold to over fold, compared with ciprofloxacin [ 4546 ].
For the 6-amino compounds as well, the overall potency is highly dependent on substituents at positions C-7 and C Similar to the fluoroquinolones, a free methyl and probably a methoxyat position 8 enhances gram-positive activity, at least in vitro.
Also, the cyclopropyl substituent at position 1 is the most advantageous for both the 6-H and 6-NH2 based drugs. As for position 5, the in vitro affects seen with modifications at position 1 are not always mirrored by changes to in vivo activity when tested in an animal model. Interestingly, the dissociation between in vitro activity and in vivo potency does not appear to be solely related to oral bioavailability, because a similar finding of lower than expected biological activity was observed for at least one of these compounds regardless of whether it was administered orally or subcutaneously to mice [ 45 ].
Structure-activity relationships of the fluoroquinolones.
This position is considered to be one that directly interacts with DNA gyrase [ 41 ], or topoisomerase IV. The optimal substituents at this position have been found to be groups that contain, at a minimum, a 5- or 6-membered nitrogen heterocycle. The most common of these are aminopyrrolidines and piperazines. Placement of a aminopyrrolidine improves gram-positive activity, whereas a piperazine generally enhances potency against gram-negative bacteria. Alkylation -CH3 of the 5-membered or 6-membered heterocycle pyrrolidines and piperazines, respectively also enhances activity against gram-positive bacteria [ 2139 ].
Adding a methyl at C-2 or an amino at position 6 of an azabicyclohexane ring substituent here increases activity against T. New 2-pyridone additions to the 7-pyrrolidinyl ring have improved activity against staphylococci and anaerobes, but diminished effectiveness against important gram-negative bacilli, such as P. Specific placement of amino or methyl groups on the position 7 substituent heterocycles has similar resultant effect on the in vitro activity of 6-H—quinolones [ 44 ].
A recent interesting observation is that increased bulkiness here R-7 appears to confer protection from the efflux exporter proteins of bacteria, and diminishes the likelihood of bacterial resistance in wild-type bacterial strains [ 484949a ]. Bulk here also increases anti-anaerobic activity. Moxifloxacin and trovafloxacin are the currently available agents with the greatest bulk at this position, and they appear least affected by reserpine-inhibited exporter proteins [ 484949a ].
This position is considered to affect overall molecular stearic configuration, similar to position 5 [ 38 ]. Therefore, changes made here affect target affinity, probably by altering drug access to the enzyme or DNA binding sites. A free halogen F or Cl here may improve activity against anaerobes [ 39 ].
Halogen substituents, as well as a methyl or methoxy also increase the in vitro activity against gram-positive cocci, even in those bacteria resistant to older fluoroquinolones [ 44 ]. Interestingly, the R-8—substituted quinolones also exhibit enhanced bacteriostatic and lethal activities against GyrA mutants of both E. Of particular interest is the observation that specific changes here appear to dramatically alter the initial target in fluoroquinolones, at least in gram-positive cocci.