Agui H, Mitani T, Izawa A, Komatsu T, Nakagome T. Studies on quinoline derivatives and related compounds. 5. Synthesis and antimicrobial activity of novel. Structure-activity relationship (SAR) requirements are typically based on substitution of the lactone .. Diuretics. (a) Thiazides and related sulfonamides (e) Metformin: Chemically it is N, N-dimethyl biguanidine. It has no. Moses R. Repaglinide in combination therapy with metformin in type 2 diabetes. The structure—activity relationship between peroxisomeproliferator-activated.
Structure-activity relationships of the fluoroquinolones.
About 9 mL of blood collected in two tubes from each animal, one with EDTA for obtaining plasma, the second was allowed to clot for 30 min. Then, the blood in two tubes was centrifuged at 3, rpm for 15 min to separate serum and plasma for different biochemical analyses. Triglycerides, cholesterol and high density lipoprotein-cholesterol HDL-c were determined using the commercial kits. Low density lipoprotein-cholesterol LDL-c levels were calculated by using the following formula of Muruganandan et al.
Volatile low density lipoprotein-cholesterol VLDL-c levels were calculated by using the following formula of Prakasam et al. The risk ratio was calculation by dividing the total cholesterol by HDL-c.
Antioxidant abilities Assessment of lipid peroxidation as oxidative indicator: Bioindicator in tissues the thiobarbituric acid reactive substances TBARS levels as an index of malondialdehyde MDA production were measured by the method described by Ohkawa et al. MDA, an end product of lipid peroxidation reacts with TBA-TCA complex to form a colour complex at high temperature exhibiting an absorption maximum at nm. Determination of enzymatic and non-enzymatic antioxidants: Illumination of riboflavin in the presence of O2 and electron donor like methionine generates superoxide anions and this has been used as the basis of ability of SOD.
The reduction of NBT by superoxide radicals to blue colour formazan was followed at nm [ 17 ]. Reduced glutathione level GSH as nonenzymatic antioxidant was estimated based on the method of Beutler et al. Determination of blood glucose level, Hb, HbA1c: Glucose was estimated by O-toluidine method of Sasaki et al.
Hb was estimated by cyanmethaemoglobin method of Drabkin and Austin [ 20 ]. HbA1c was estimated by the method of Sudhakar and Pattabiraman[ 21 ] with modification by Bannon [ 22 ].
Insulin level and C-peptide: Insulin in pancreatic homogenates was determined by Immulite Insulin Diagnostic Products Corporation, Los Angeles which depends on a two-site chemiluminescent enzymelabelled immunometricability [ 23 ] Serum C-peptide was measured by radioimmunoassay Medgenix Diagnostics as described by Kumar et al. All chemicals and reagents were of pure analytical grade. At time of death, pancreas tissues were dissected, cleared of lymph nodes and fat, blotted, washed from blood and weighed.
The pancreas was immediately homogenized in 5 ml cold 2 M acetic acid for 5 s. The extract was centrifuged at 15 r. The third portion of the pancreas was immediately cut into small cubes and transferred to ice-cold fixation buffer 1. The synthesized Cr III complex is leaf green and soluble in dimethylsulfoxide and dimethylformamidepartially soluble in hot methanol and insoluble in water and some other organic solvents.
The slightly electrolytic value may be due to the contribution of the one chloride anion in the outer sphere of chelating skeleton of the Cr III metformin complex. The infrared absorption bands are one of the important tools of analyses used for determining the mode of chelations.
The most significant bands of metformin HCl ligand can be classified into two groups: According to the two fundamental vibrational groups mentioned above, the metformin HCl free ligand can be interpreted as follows: Usually the frequency of this vibration decreases in the presence of the hydrogen bond [ 28 ].
The broad bands at and and cm-1 have been assigned to N-H asymmetric and symmetric stretching vibrations, respectively [ 28 ]. The band at cm-1 has been assigned for NH2 in the plane deformation vibrations [ 28 ]. The bands of the medium-to-weak intensities atand cm The medium-to-weak intensity bands in the IR spectra at, and cm Medium-toweak intensity bands at,and cm This indicates that metformin is coordinated to the metal ions through the nitrogen atom of the imino group. The infrared spectra of distinguish bands of water molecules concerning hydrated Mfn-HCl complex exist with overlapping the characteristic bands of the amino group.
Metformin hydrochloride free ligand has absorption in the ultraviolet regions at, and nm and in some cases these bands extends over to higher wavelength region due to conjugation. New bands due to charge transfer spectra from metal to ligand M—L or ligand to metal L—M can be observed and this data can be processed to obtain information regarding the structure and geometry of the complexes .
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.
Structure-activity relationships of the fluoroquinolones.
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. 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. 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.
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