dihydropyridines and Hemolysis

The aim of this study is to synthesize, characterize and biological evaluation of 3-ethyl 5- methyl2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate derivatives.. An efficient synthesis of two series of novel carbamate and sulfonamide derivatives of amlodipine, 3-ethyl 5-methyl 2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (amlodipine) 1 were chemical synthesized process.. In this process, various chloroformates 2(a-e) and sulfonyl chlorides 4(a-e) on reaction with 1 in the presence of N,N-dimethylpiperazine as a base in THF at 50-550 oC, the corresponding title compounds 3(a-e) and 5(a-e) in high yields. Furthermore, the compounds 3(a-e) and 5(a-e) were evaluated for antioxidant activity (DPPH method), metal chelating activity, hemolytic activity, antioxidant assay (ABTS method), cytotoxicity, molecular docking and in silico ADMET properties.. Results revealed that 5a, 5e, 3d, 3a and 5c exhibited high antioxidant, metal chelating activities, but 5a, 5e and 3d exhibited low activity. The molecular docking studies and ADMET of suggested ligands showed the best binding energies and non-toxic properties.. The present in silico and in vitro evaluations suggested that these dihydropyridine derivatives act as potent antioxidants and chelating agents which may be useful in treating metals induced oxidative stress associated diseases.

Topics: Animals; Antioxidants; Chelating Agents; Computer Simulation; Dihydropyridines; Hemolysis; Molecular Docking Simulation; Structure-Activity Relationship

The aim of this work was to study the complexation capability of new sulfobutyl ether-alkyl ether (SBE-AE-CD) mixed beta- and gamma-cyclodextrin derivatives with a series of structurally related steroids (6alpha-methylprednisolone, prednisolone, triamcinolone, D(-) norgestrel and hydrocortisone) and a number of dihydropyridine calcium channel blockers (nimodipine, nitrendipine, nifedipine) that traditionally interact poorly with other cyclodextrins (CDs). The effect of the total degree of substitution (TDS) and of the length of the alkyl side chain on binding capacity of these new modified CDs was evaluated as was their ability to induce red blood cell hemolysis. An attempt was made to correlate hemolysis to surface activity. Binding constants between the SBE-AE-CDs and selected molecules were determined by spectroscopic studies, and only in few cases by solubility studies. Hemolysis percentage was determined using citrated rabbit blood and citrated human blood with UV analysis. The surface activity was measured with a tensiometer. A significant improvement in the binding capacity between various substrates and the new SBE-AE-CDs was observed when compared to the SBE-CDs. The length of the alkyl chain and total degree of alkylation affected the binding with the relationship being complex. For most compounds, an intermediate degree of substitution appeared to be advantageous. The hemolysis studies showed that some of the derivatives may induce hemolysis and this correlated with higher surface activity for some but not all of the derivatives.

Topics: Algorithms; Animals; beta-Cyclodextrins; Calcium Channel Blockers; Cyclodextrins; Dihydropyridines; Erythrocytes; Ethers; Hemolysis; Rabbits; Solubility; Spectrophotometry, Ultraviolet; Steroids; Surface Tension

Ten 4-aryl-1,4-dihydropyridine and three 4-aryl-1,2,3,4-tetrahydropyrimidin-2-one derivatives have been synthesized and examined for their activity against pathogenic strains of Aspergillus fumigatus and Candida albicans. Although none of the three compounds belonging to pyrimidin-2-one series showed any activity against two pathogens, two of the compounds of the dihydropyridine series, that is, diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarboxylate and dimethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarboxylate, exhibited significant activity against A. fumigatus in disc diffusion, microbroth dilution and percent spore germination inhibition assays. The most active diethyl dihydropyridine derivative exhibited a MIC value of 2.92 microg/disc in disc diffusion and 15.62 microg/ml in microbroth dilution assays. The MIC(90) value of the most active compound by percent germination inhibition assay was found to be 15.62 microg/ml. The diethyl dicarboxylate derivative of dihydropyridine also exhibited appreciable activity against C. albicans. The in vitro toxicity of the most active diethyl dihydropyridine derivative was evaluated using haemolytic assay, in which the compound was found to be non-toxic to human erythrocytes even at a concentration of 625 microg/ml. The standard drug amphotericin B exhibited 100% lysis of erythrocytes at a concentration almost 16 times less than the safer concentration of the most active dihydropyridine derivative.

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candida albicans; Dihydropyridines; Erythrocytes; Hemolysis; Humans; Hydroxylation; Microbial Sensitivity Tests; Microwaves; Molecular Structure; Pyrimidines

1,4-Dihydropyridine derivatives possess various physiological activities but their mechanism of membranotropic action is not completely investigated yet. We have examined the membranotropic effects of 4-beta-pyridyl-1,4-Dihydropyridine derivatives containing different length alkyl chain substituent at N-quaternised 4-beta-pyridyl moiety. The results show the relation between incorporation of 1,4-dihydropyridine derivatives in the liposomal membranes and influence on bilayer fluidity. The compound with hexadecyl (C16H33) substituent in the 4-beta-pyridyl moiety possess the most pronounced incorporation ability and fluidizing effect. This compound causes the remarkable release of fluorescent probe calcein from liposomes and induces the hemolysis of human erythrocytes as well. The obtained results suggest that the length of alkyl chain at quaternized 4-beta-pyridyl moiety is significant for the expression of membranotropic effects of tested compounds.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Dihydropyridines; Erythrocyte Membrane; Fluoresceins; Fluorescent Dyes; Hemolysis; Humans; Lipid Bilayers; Liposomes; Membrane Fluidity; Spectrometry, Fluorescence; Structure-Activity Relationship

The effects of dihydropyridine compounds nimodipine, nicardipine and NB818 (isopropyl methyl-6-carbamoyloxymethyl-4-(2,3-dichlorophenyl)-1,4-dihydro-2-methyl- 3,5- pyridine-dicarboxylate) on erythrocyte membranes have been studied. These compounds showed protective effects against hypotonic haemolysis, but not against heat-induced haemolysis. An increase in deformability of erythrocytes by these calcium antagonists was observed using a capillary tube centrifugal method. The erythrocytes showed slight stomatocytosis after 30 min of incubation with calcium antagonists, but did not show significant changes in mean corpuscular volume and ATP levels.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Erythrocyte Membrane; Hemolysis; Male; Microscopy, Electron, Scanning; Nicardipine; Nimodipine; Rats; Rats, Inbred Strains