Synthesis and Analgesic Activity of Ibuprofen L-Ascorbic Acid Ester . Pharmacokinetics of Levofloxacin Hydrochloride Eye Drops in Aqueous Advances of Quinolones as Potent HIV inhibitors and Their Structure-activity Relationships. Recently it was claimed that immediate hypersensitivity to quinolones is frequently Recognition of 'Small' Molecules of Widely Varying Structures and Activities. We have a lot of chemotherapeutic antimicrobials that have activity Basic Structure of 4-quinolones (Short for 4-oxo-1, 4-hydroquinoline); 6.
Systems Adverse drug reactions can involve specific organ systems, such as the GI tract, the CNS, or the kidneys, or may represent a hypersensitivity reaction. For the fluoroquinolone class of antimicrobials, the most common adverse effects involve the GI tract, skin, CNS, and events that resemble allergic reactions [ 1415 ].
Here we review the individual systems and the types of adverse events that have been described, as well as their postulated mechanisms of action. The adverse events reported for fluoroquinolones involving the GI tract are usually mild and do not often require discontinuation of therapy. It is not presently clear that any structure-adverse event relationship exists, and adverse effects associated with the GI tract are thought to be due to either GI irritation, a CNS effect, or both [ 1216 ].
Although pseudomembranous colitis is certainly an unusual adverse event, it has been reported with quinolone use [ 2324 ]. The rank order of fluoroquinolone agents for GI adverse effects is as follows: Adverse events involving the CNS are the second most frequently encountered form of quinolone toxicity and are usually divided into minor and serious events.
CNS effects can occur as a result of either direct action of a drug on CNS receptors or as a result of interaction between a quinolone and another pharmacologic agent. Direct actions themselves can be further divided into blocking of the GABA receptor and primary excitatory effects mediated via the N-methyl-D-aspartate adenosine NMDA receptor mechanisms [ 1826 ].
This can be augmented by the presence of 4-biphenylacetic acid, which is an active metabolite of the nonsteroidal agent fenbufen [ 27 ]. This unfortunate interaction was dramatically highlighted when 7 Japanese patients experienced seizures while on enoxacin and fenbufen therapy [ 28 ]. Unsubstituted piperazines exhibit the greatest degree of binding, with pyrrolidyl quinolones intermediate in their effect and bulky alkylated side chains showing the least amount of binding [ 1229 ].
It has been suggested that the likelihood of convulsions occurring in animal models is more closely related to the NMDA receptor and may explain the higher incidence of CNS effects seen in trovafloxacin postmarketing surveillance data.
This receptor has been postulated to play a role in seizures secondary to fluoroquinolones in animals and may be prevented with the use of NMDA antagonists [ 31 ]. We alluded to drug interactions as a possible mechanism for CNS toxicity, and the example we gave was of fenbufen and its metabolite 4-biphenylacetic acid enhancing quinolone binding to the GABA receptor.
Another example is the interaction between fluoroquinolones and theophylline. Theophylline is metabolized by cytochrome P enzymes that in turn may be inhibited by certain fluoroquinolones. Inhibition of theophylline metabolism would inevitably result in CNS toxicity that might include seizures [ 1232 ].
Other types of drug interactions will be discussed in a separate section. The rank order of fluoroquinolones associated with adverse drug reactions of the CNS is as follows: Adverse events involving the liver vary from mild elevation of liver enzymes to cholestatic syndromes to hepatic failure resulting in liver transplantation or death.
Recent events involving trovafloxacin have once again shown how potentially dangerous clinical trials involving new chemotherapeutic agents can be.
The trovafloxacin issues are discussed in a separate section that deals with unexpected adverse events, as were seen with trovafloxacin and one of its predecessors, temafloxacin. These are usually mild elevations that are not associated with any overt clinical findings, and the elevation typically reverts to normal levels when the drug is discontinued.
Hepatotoxicity can occur as the result of a direct chemical effect because many drugs are concentrated in the liver; hepatotoxicity may also occur by drug allergy or hypersensitivity reactions. The use of skin as a category is, in a sense, misleading because the skin is not directly involved by the drug in the way that the liver or CNS are.
Instead, it often represents a final common pathway as a means of expression of toxicity mediated either by an allergic reaction, a histamine release phenomenon, or photosensitivity.
Drug allergy can be expressed in a number of ways, and skin reactions vary from a mild rash to urticaria to a severe exfoliative dermatitis. The overall rate of adverse events involving skin with fluoroquinolone use is 0. As part of allergic or hypersensitivity responses to foreign molecules, anaphylactic reactions may occur. The former is rare, requires previous exposure to the offending fluoroquinolone, and is dependent on the presence of photohaptenic substituents [ 33 ].
The clinical manifestations typically appear a day or so after exposure. This is in contrast to phototoxic reactions, which are more frequent and can appear in anyone, even with initial exposure, providing that there was sufficient exposure to ultraviolet light and that a drug known to cause it was used by the patient.
The mechanism of phototoxicity is believed to be due to the generation of singlet oxygen and toxic radicals. After exposure to ultraviolet A radiation, certain fluoroquinolones induce toxic agents that can in turn damage cell membranes, resulting in an inflammatory response [ 3435 ].
The greatest degree of phototoxicity occurs when the X8 substituent is a halogen, particularly fluorine, and a bulky side chain; a methyl group at R5 may contribute as well [ 1222 ]. The rank order for phototoxicity is as follows: The main area of interest relating to cardiac toxicity is prolongation of the QT interval.
This phenomenon was well described with erythromycin, and it appears that it may be an effect of fluoroquinolones as a class. Certain drugs, such as rifampin, rifabutin, isiniazid, clofazimine, and some FQs, strongly or moderately reduced the anti-MAC activity [ 59 ]. The major problem linked with the use of FQs is the increased incidence of FQ- resistant strains of M.
Pharmacokinetics The common adverse effects associated with the use of FQs are gastrointestinal disturbances, nervous system complaints dizziness, headacheand allergic reactions skin rashes and pruritus [ 6061 ]. The use of several FQs have been severely restricted because of advers effects; clinafloxacin causing phototoxicity and hypoglycaemia, SPFX causing phototoxicity [ 62 ].
Grepafloxacin has been withdrawn from the market due to prolongation of the QTc interval. Drug interactions are limited and are infrequent between FQs and other antit-TB drugs [ 64 ], however FQ absorption may be reduced when co administered with antacids containing multivalent cations [ 6566 ]. The mechanism by which quinolones enter the bacterial cell is complex [ 67 ].
The physicochemical properties of quinolones hydrophobicity, charge or molecular mass are important factors for bacterial cell penetration and play a different role in Gram-negative and Gram-positive bacteria.
Increasing molecular mass and bulkiness of substituents at C-7 position hinder penetration of quinolones into Gram-negative bacteria through the porin channels, although hydrophobic molecules appear to enter via the lipopolysaccharide or across the lipid bilayer [ 68 ]. Gram-positive bacteria do not possess an outer membrane, therefore lacking outer membrane proteins and lipopolysaccharide.
Intracellular accumulation observed in Gram-positive bacteria e. The unique cell wall structure of mycobacteria is rich in long-chain fatty acids such as C60 to C90 mycolic acids [ 39 ].
Mycolic acids are covalently linked to the peptidoglycan-associated polysaccharide arabinogalactan. Moreover, mycobacterial porins, the water-filled channel proteins which form the hydrophilic diffusion pathways, are sparse [ 70 ]. A major porin of M. The mycobacterial cell wall functions as an even more efficient protective barrier than the outer membrane of gram-negative bacteria and limits the access of drug molecules to their cellular targets Table 2.
Classification on the basis of spectrum of activity. Structure-activity relationship The minimal quinolone structure consists of a bicyclic system with a substituent at position N-1, a carboxyl group at position 3, a keto group at position 4, a fluorine atom at position 6 in case of FQs Figure 1 and a substituent often nitrogen heterocycle moiety at the C Normally in position 2 there are no substituents, various 1-methylalkenyl-4 1H quinolones have been investigated as anti-TB agents [ 7273 ].
The DNA gyrase is most likely the only target of quinolone in M. The DNA supercoiling inhibition assay may be a useful screening test to identify quinolones with promising activity against M. Some quinolones showed high inhibitory activity against M. Structure activity relationship SAR showed that C-8 with or lacking a substitution, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are advantageous structural features in targeting M.
The quinolones that showed high potency against M. Compounds grepafloxacin, gemifloxacin, TVFX, and the des[ 6 ] FQ garenoxacin with high activity against pneumococci showed only moderate activity against M. In contrast to its effects against pneumococci, the presence of a group at C-5 [ 75 ]. Moreover, the presence of a naphthyridone core N-8 in gemifloxacin, which has the lowest MIC against gram-positive bacteria, seems adverse effect for a interaction with M.
Similarly, the naphthyridones tosufloxacin and enoxacin, were only moderately active [ 76 - 84 ]. The substituent at N-1 and C-8 positions should be relatively small and lipophilic to enhance self-association.
While at C-6 and C-7 positions at fluorine atom and amino group, respectively, appear to be the best. In particular fluorine atom at C-6 improves cell penetration and gyrase affinity [ 6685 ]. The nature of substituent at C-7 position has a great impact on potency, spectrum, solubility and pharmacokinetics. Almost all quinolones have nitrogen heterocycles linked to this position through the heterocyclic nitrogen, extensively investigated are piperazinyl and its 4-substituted derivatives [ 86 ].
The resulst revealed that usually the increase of lipophilic character of the side chain at C-7 improves the anti-TB activity, without inducing cytotoxicity as demonstrate for balofloxacin ethylene isatin derivatives [ 87 ].
Furthermore, with regard to the substituent at N-1 position, studies confirm that the anti-TB activity is higher for the cyclopropyl and tert-butyl goup than for the 2,4-difluorophenyl and others groups [ 8990 ].
Ciprofloxacin and gatifloxacin 7-substituted derivative.
Quinolones: structure-activity relationships and future predictions.
Extensive SAR study showed that an increase in the activity of a given quinolone against gram-positive bacteria does not necessarily lead to increased activity against M. ABT was also more potent than TVFX and CPFX against most quinolone-susceptible pathogens responsible for respiratory tract, urinary tract, bloodstream, and skin infections and against anaerobic pathogens. It was significantly more active than other quinolones against quinolone-resistant gram-positive strains.
Furthermore ABT was active against Chlamydia trachomatis, indicating good intracellular penetration. However the activity of ABT against M.
Synthesis of Related Substances of Rocuronium Bromide - Technische Informationsbibliothek (TIB)
The HSR is a newly synthesized quinolone with superior activity against gram-positive cocci [ 89 ]. Conclusion Quinolines are second-line anti-TB drugs, since their use in TB treatment still remains controversial [ 94 ]. On the contrary, they are suggested and recommended in managing MDR-TB, due to the fact that they have a broad and potent spectrum of activity and can also be administered orally, giving a better chance of cure and preventing the development and spread of further resistance [ 95 ].
However, quinolones remain one of the most widely prescribed antibiotics. In conclusion, we can confirm that in general quinolones are particularly adapted to be used as antitubercular agents. The history of quinolones In Fluoroquinolone Antibiotics. Fluoroquinolones tuberculosis and resistance. Fluoroquinolone resistance in patients with newly diagnosed tuberculosis.
N Engl J Med. World Health Organization HIV infection associated tuberculosis: Clin Infect Dis, ; Accelerated course of human immunodeficiency virus infection after tuberculosis. Activity in vitro of the quinolones. In Quinolone Antimicrobial Agents, 2nd edn. The clinical use of fluoroquinolones for the treatment of mycobacterial diseases. Medical Letter Gatifloxacin and moxifloxacin: Med Lett Drugs Ther.
- Mechanisms of Antimicrobial Toxicity
- Original Research ARTICLE
Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump. Management of fluoroquinolone resistance in Pseudomonas aeruginosa: Outcome of monitored use in a referral hospital.
Int J Antimicrob Agents. Drlica K, Zhao X. Performance in test and external validation sets are reported in Supplementary Table 1.
Manually extracted structural alerts SAs with the total number of occurrences and the number and percentage of true positive TP in the training set. Totally, we identified 13 SAs, 11 of them considered hepatotoxic. SA identified with ID 1 N-containing heterocycles aromatic compounds pyridine, pyrazine, pyrimidine matched the highest number of compounds in the training 57test 19 and external validation 9 sets. Its performance in the training and in the test sets was high It did not match any chemicals in the external validation set.
In the test and external validation sets it did not match any compounds. Although we only used positive compounds to extract SAs, we labeled the SAs identified by ID 12 and 13 as non-hepatotoxic since they matched more experimentally non-hepatotoxic compounds than hepatotoxic ones Figure 1step 5. In order to keep only the reliable SAs, we deleted those with percentages of TP below the arbitrary threshold of The complete list of SAs for hepatotoxicity and non-hepatotoxicity is available in Supplementary Table 2; the statistical performance of each SA, in terms of total number of occurrences and the number and percentage of TP in the training, test and external validation sets are also provided.
Due to the relative high number of SAs extracted with SARpy software compared to the number of molecules available for the test and external validation sets, the total occurrences of 34 and 37 out of 75 SAs were null in the test and external validation set, respectively.
Decision Tree After identifying the SAs, we established a reasonable strategy for manually building the model basing on the expert-based knowledge. Figure 2 shows the decision tree we applied for building the model for the prediction of hepatotoxicity. If more than one SAs is found, the prediction depends on the number of SAs: Since it is preferable to overestimate hepatotoxicity rather than not to recognize unsafe compounds, the overall model's architecture followed a conservative approach.
Decision tree developed for the hepatotoxicity model. Percentages of correctly predicted, wrongly predicted and non-predicted unknown compounds in the training, test and external validation sets.
Performance of the model in the training, test and external validation sets. Out of compounds that were present in the training set, were not predicted by the model unknown, non-predicted.
For 91 compounds in the test set molecules the model did not provide any prediction unknown, non-predicted48 compounds were correctly identified as hepatotoxic TP and 15 as non-hepatotoxic TN.
The number of experimentally negative non-hepatotoxic compounds wrongly predicted as hepatotoxic FP was 30 and the number of positive compounds hepatotoxic wrongly predicted as negative FN was 6.
In the external validation set compounds59 chemicals were not predicted by the model unknown, non-predictedthe numbers of TP and TN was 35 and 5 respectively. Figure 3 shows percentages of correctly predicted and wrongly predicted compounds in the training, test and external validation sets.
Discussion Limitations and Weaknesses of Experimental Hepatotoxicity Data High-quality and reliable biological data are essential in order to build predictive models to provide relevant information about the toxicological behavior of a substance.