Clin Infect Dis. Sep 15;33 Suppl 3:S Quinolone molecular structure- activity relationships: what we have learned about improving antimicrobial. longer QTc interval than patients treated with levetiracetam . activity, in agreement with the study of Krishnan and in order to evaluate the correlation between PR and QTc Overall, these findings may reflect cardiac structural changes and/or alterations in autonomic tone that deserve closer study. Seizures induced by pentylenetetrazole increased the activity level of calpain, Levetiracetam is an atypical antiepileptic drugs that considerably differs from that inhibition of calpain activity can preserve cytoskeletal structure of neurons. .. Enhanced susceptibility of pentylenetetrazole kindled mice to quinolone effects.
Effects of norfloxacin on DNA metabolism in Pseudomonas aeruginosa. 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. 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.
However, its precise mechanism of action is still not fully elucidated. Carbamazepine CBZa traditional antiepileptic drugs; is widely used as a first-line drug in the management of tonic-clonic seizures. It blocks sodium channels during rapid, repetitive, sustained neuronal firing Roger et al. It is known that neuronal death resulting from seizures can be initiated by excessive glutamate releasec that activates postsynaptic N-methyl-D-aspartate NMDA receptors, thereby triggering large calcium influx.
This in turn results in the activation of intracellular proteases such as calpain, caspase and cathepsin Saido et al.
In addition, excess intracellular calcium results in mitochondrial damage and cytochrome c release which ultimately leads to caspase activation Zhu et al. Caspases activate calpain by mediating the degradation of calpastatin, an endogenous inhibitor of calpain proteases Wang, ; Sorimachi and Suzuki, and additionally caspases might be activated by calpain proteases Yamashima, Activated calpain causes a limited degradation of a variety of biologically important proteins including; cytoskeletal proteins, membrane integral proteins, certain enzymes and transcription factors, components in cell adhesion and signaling pathways Molinari and Carafoli, Calpain has been implicated in various types of acute neuro-degeneration, particularly those induced by trauma, ischemia and neural excitotoxicity Blomgren et al.
Caspases also have a role in neurofibrillary tangle formation Rohn et al. Calpain antagonist can prevent breakdown of neurofilamants and spectrin and reduce the traumatic brain injury, suggesting that inhibition of calpain activity can preserve cytoskeletal structure of neurons. The calpain activity in vivo is controlled by calpastatin Kawasaki et al.
The upregulation of several members of the calpain family is involved in a diverse range of biological processes and diseases, indicating that this family of proteases has important therapeutic potential. However, little information is available on the role of cysteine proteases; calpain, caspase 3 and cathepsin B pathway in convulsion. To our knowledge, calpain antagonist calpastatin has not been investigated in fully kindled rats as a model of convulsion.
Moreover, the information on possible involvements of cysteine proteases in the mechanism of action of atypical antiepileptic drugs; LEV and traditional antiepileptic drugs; CBZ is still lacking. Therefore, the main objectives of the present study were the followings: They were housed in cages under conventional laboratory conditions. The animals were fed a standard rat pellet diet and water ad libitum. All animal procedures were undertaken according to the international guidelines of proper experimental animal handling.
All chemicals and reagents used in this study were of higher analytical grade. The following drugs and chemicals were obtained from commercial sources: Pentylenetetrazole Sigma Chemical Company, St. Total protein kit Randox, Mississauga, Ontario, Canada. Seizures were induced by intraperitoneal i. The selected concentration of PTZ in the present study was based on data from our preliminary experiments.
The animals were then placed in isolated cages and observed for 30 min for the onset of convulsions. The intensity of the seizure was scored as follows: The maximum response was recorded for each animal De Sarro et al.
Structure-activity relationships of the fluoroquinolones.
Rats that convulsed in response to the kindling treatment on day l were excluded from the study. When a rat exhibited stage 4 seizures for three times, it was considered fully kindled, treatment with PTZ was discontinued and the animal was included in the study De Sarro et al.
Effects of treatment with different doses of CBZ or LEV or CS on brain proteases activity, seizure severity and motor function in normal and PTZ-treated rats Effect of treatment with different doses of the selected drugs on normal rats: Rats were randomly allocated into 10 groups of 8 animals each. One group of rats served as control saline treated group while the other 9 groups were treated with different doses of CBZ 50, and mg kg-1 p. De Sarro et al.
Sluzewska and Chodera, or CS 1. According to the manufactures instruction, Calbiochem. Effects of treatment with different doses of the selected drugs on PTZ-treated rats: Seizure were induced by PTZ 49 mg kg-1, i. The rats that showed convulsion at the end of the treatment period were included in the study. Fully kindled rats were randomly divided into 10 groups of 8 animals each.
After a three days PTZ free period, one group was kept as fully kindled rats, served as kindled control and received only vehicle while the other nine groups kindled rats were treated with the different doses of CBZ 50, and mg kg-1, p. A vehicle control injection was given every second day to ensure that the rats continued to respond with kindled seizures in the absence of anticonvulsant drugs. The animals were then observed for 30 min and the seizures severity test was recorded after treatment with the same above mentioned different doses of CBZand 50 mg kg-1, p.
Moreover, rats were also evaluated for their impaired motor function. In another 10 groups of 8 animals each, one group served as control and received only vehicle. The other nine groups were pretreated for two weeks with different doses of CBZ 50, and mg kg-1, p. During kindling acquisition, all the 10 groups received PTZ 49 mg kg-1 i. Preparation of brain tissue homogenates: At the end of the treatment protocol, the animals were deeply anaesthetized using light ether anesthesia and sacrificed by decapitation.
Brains were removed, placed on ice and snap-freeze. Extreme care was taken in consideration to keep samples as cold as possible during dissection of hippocampus and preparation of homogenates and to work rapidly to reduce formation of post-mortem artefacts.
Measurement of proteases activity Calpain, Caspase 3 and Cathepsin B: The level of calpain, caspase and cathepsin B activity were determined fluorometrically using fluorescent assay commercial kits according to the manufactures instruction Biovision, Linda Vista Avenue, USA. At the end of the treatment protocol, 5 rats from each group were anesthetized with sodium pentobarbital mg kg The brains were removed from the skull and fixed in the same fixative for 24 h.
Table 2 shows that induction of seizures using PTZ resulted in freezing response during the evoked ictal discharge. With repeated activation, the seizures response became generalized to the point of driving bilateral clonic seizures typically referred to as stage 5 seizures.
The early stages 1 and 2 were primarily associated with facial and oral activity, including eye closure and blinking followed by head bobbing and drooling.
As focal seizures activity increased during the early kindling trials, mild stage 3 forelimb clonus appeared. With the time, the seizures become more fully generalized and presented with stronger clonus and rearing stage 4 and rearing and falling full stage Seizures were induced by PTZ 49 mg kg-1, i.
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The animals were then placed in isolated cages and observed for 30 min for the incidence and onset of convulsions. Treatment of normal rats with CBZand 50 mg kg-1, p. However, treatment of fully kindled rats with different doses of the selected drugs caused marked decrease in the kindling behavior as indicated by the decrease in seizure severity Table 3. These effects varied widely among the different drugs used in the study.
CS was the most potent and effective drug in inhibiting the PTZ-induced seizures at all tested dose 1. LEV also produced a dose dependent inhibition of seizures occurrence with maximum reduction observed at 54 mg kg-1 p. These findings suggest that inhibition of cysteine proteases may be involved in the seizures induced by PTZ.
The PTZ induced seizures resulted in the inability of the kindled rats to maintain their equilibrium for three times when placed on Rota rod for motor function evaluation Data not shown. The intensity of the seizure response was scored on the following scale: The seizures severity test was repeated after administration of different doses of CBZand 50 mg kg-1, p.
Effects of PTZ administration 49 mg kg-1, i. The administration of PTZ 49 mg kg-1, i.
Structure-activity relationships of the fluoroquinolones.
Effects of treatment with antiepileptic drugs on calpain activity in hippocampus of PTZ-kindled rats. Mild to moderate activity exhibited against P.
The newer FQs are used as single agents for treatment of community-acquired pneumonia [ 11 ]. However, have decreasing susceptibility of S. Bone, Joint, and Soft Tissue Infections The treatment of chronic osteomyelitis requires prolonged antimicrobial therapy with agents active against S. The FQs may be used appropriately in some cases [ 25 ].
Bone and joint infections may require treatment with FQs. Dosage should be reduced for patients with severely impaired renal function.Intro to Bacteria & Antibiotics: Quinolones
Ciprofloxacin CPFX should not be given to children or pregnant women. Failures have been associated with the development of resistance in S. In diabetic foot infections, which are commonly caused by a mixture of bacteria including gram-negative rods, anaerobes, streptococci, and staphylococci, the FQs in combination with an agent with anti-anaerobic activity are a reasonable choice.
Other Infections Ciprofloxacin CPFX wide usage for the prophylaxis of anthrax and also effective for the treatment of tularemia [ 2627 ]. The FQs may be used as part of multiple-drug regimens for the treatment of MDR-TB and for the treatment of atypical mycobacterial infections as well as M.
Quinolones, when used as prophylaxis in neutropenic patients, have decreased the incidence of gram-negative rod bacteremias. Diarrhea and antibiotic-associated colitis have been unusual. CNS side effects like mild headache and dizziness, in 0. Rarely, hallucinations, delirium, and seizures have occurred, predominantly in patients who also were receiving theophylline or a nonsteroidal anti-inflammatory drug NSAIDs.
Ciprofloxacin CPFX and pefloxacin inhibit the metabolism of theophylline, and toxicity from elevated concentrations of the methylxanthine may occur. Rashes, including photosensitivity reactions, also can occur.
Achilles tendon rupture or tendinitis has occurred rarely. Renal disease, hemodialysis, and steroid use may be predisposing factors [ 28 ]. The use of FQs in children has been contraindicated for this reason. However, children with cystic fibrosis given CPFX, norfloxacin, and nalidixic acid have had few, and reversible, joint symptoms [ 30 ]. Leukopenia, eosinophilia, and mild elevations in serum transaminases occur rarely. Quinolones probably should be used only with caution in patients treated with amiodarone and quinidine, procainamide as antiarrhythmics Table 1.
Approved clinical uses for selected fluoroquinolones. Quinolones and Chemotherapy Quinolones are classified in four generations. Most recent FQs are being evaluated as potential anti-TB drugs, also for the shorten TB treatment duration, one of the major strategies for TB control [ 32 ].
Fluorine-containing nalidixic acid derivatives, the FQs, were introduced into clinical practice in the s [ 31 ]. Norfloxacin, the first of a new generation of FQ are antibacterial activity [ 34 ]. Substitutions of the FQ molecule resulted in the development of CPFX, a widely used broad spectrum antimicrobial agent [ 35 ].
Several modifications of the FQ structure have been attempted in order to develop new expanded antimicrobial agents with improved pharmacokinetic profiles, decreased resistant mutants, reduced adverse effects, and improved efficacy [ 3637 ].
Last-generation FQs share a broad-spectrum antimicrobial activity covering aerobic and anaerobic Gram-positive and Gram-negative bacteria as well as mycobacteria M. Fluoroquinolones are widely used for the treatment of infections of the respiratory, gastrointestinal and urinary tracts, sexually transmitted diseases, skin and soft tissue infections and chronic osteomyelitis [ 4041 ].
New FQs are in various phases of clinical development like tosufloxacin, fleroxacin, clinafloxacin, gemifloxacin, rufloxacin, enrofloxacin, difloxacin, amifloxacin, iloxacin, temafloxacin, nadifloxacin, grepafloxacin, balofloxacin, pazufloxacin, prulifloxacin, sitafloxacin, garenoxacin, olamufloxacin [ 4243 ]. Appreciable efficacies of FQs have also been demonstrated against both M. Many new FQs indicated for the treatment of respiratory tract infections show excellent activity against MAC isolates [ 4849 ].
The value of FQs in the treatment of TB infections may be attributed to the good penetration into infected macrophages where they exert antibacterial activity [ 57 ].
Selected quinolones, on the intracellular activity against M. 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 ].