Antimicrobial,anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4-dihydropyridine derivatives

A new series of 1,4-dihydropyridine derivatives (2a–h, 3a–e, and 4a–e) were systematically designed and synthesized via ultrasound irradiation methods with easy work-up and good yields. Compounds structures were confirmed by IR, ¹H NMR, ¹³C NMR, and mass spectra. The synthesized compounds were screened for both antimicrobial and anticoagulant activities. Compound 2e (MIC: 0.25?μg/mL) was highly active against Escherichia coli and compound 2c (MIC: 0.5?μg/mL) was also highly active against Pseudomonas aeruginosa compared with ciprofloxacin. (MIC: 1?μg/mL) The antifungal activity of 2c (MIC: 0.5?μg/mL) against Candida albicans was high relative to that of clotrimazole (MIC: 1?μg/mL). Anticoagulant activity was determined by activated partial thromboplastin time (APTT) and prothrombin time (PT) coagulation assays. Compound 4-(4-hydroxyphenyl)-2,6-dimethyl-N³,N⁵-bis(5-phenyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyridine-3,5-dicarboxamide 3d (>1000?s in APTT assays) was highly active in anticoagulant screening compared with the reference of heparin.Cytotoxicity was evaluated using HepG2 (liver), HeLa (cervical), and MCF-7 (breast) cancer cell lines, with high toxicities observed for 2c (GI₅₀?=?0.02?μm) against HeLa cell line and 2e (GI₅₀?=?0.03?μm) equipotant against MCF-7 cell line. Therefore, the compounds 2e, 2c and 3d can serve as lead molecules for the development of new classes of antimicrobial and anticoagulant agent.     

Effect of new and known 1,4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic rats

Analysis of the effect of several 1,4-DHP Ca(2+) channel antagonists on experimental and clinical diabetes shows that structurally similar Ca(2+) channel antagonists can exert opposite effects on Ca(2+) influx, glucose homeostasis and insulin secretion. The influence of the Ca(2+) channel antagonists on pancreatic beta cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNAREs protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ-induced diabetic rats. The compounds tested were: 1,4-DHP derivatives cerebrocrast (1), etaftoron (2), OSI-1190 (3), OSI-3802 (4), OSI-2954 (5) and known 1,4-DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure-function relationships of the effect of 1,4-DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF(2) group in position 2 of the 4-phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5 mg x kg(-1), p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ-induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long-lasting influence on glucose metabolism, especially in STZ-induced diabetic rats.     

1,4‐Dihydropyridine derivatives without Ca2+‐antagonist activity up‐regulate Psma6 mRNA expression in kidneys of intact and diabetic rats

Impaired degradation of proteins by the ubiquitin–proteasome system (UPS) is observed in numerous pathologies including diabetes mellitus (DM) and its complications. Dysregulation of proteasomal degradation might be because of altered expression of genes and proteins involved in the UPS. The search for novel compounds able to normalize expression of the UPS appears to be a topical problem. A novel group of 1,4‐dihydropyridine (1,4‐DHP) derivatives lacking Ca2+‐antagonists activities, but capable to produce antidiabetic, antioxidant and DNA repair enhancing effects, were tested for ability to modify Psma6 mRNA expression levels in rat kidneys and blood in healthy animals and in rats with streptozotocin (STZ) induced DM. Psma6 gene was chosen for the study, as polymorphisms of its human analogue are associated with DM and cardiovascular diseases. 1,4‐DHP derivatives (metcarbatone, etcarbatone, glutapyrone, J‐9‐125 and AV‐153‐Na) were administered per os for three days (0.05 mg/kg and/or 0.5 mg/kg). Psma6 gene expression levels were evaluated by quantitative PCR. Psma6 expression was higher in kidneys compared to blood. Induction of diabetes caused increase of Psma6 expression in kidneys, although it was not changed in blood. Several 1,4‐DHP derivatives increased expression of the gene both in kidneys and blood of control and model animals, but greater impact was observed in kidneys. The observed effect might reflect coupling of antioxidant and proteolysis‐promoting activities of the compounds. Copyright © 2015 John Wiley & Sons, Ltd.     

Chemoenzymatic synthesis of enantiopure 1,4-dihydropyridine derivatives

1,4-Dihydropyridines possess a broad range of biological activities, such as the ability to control the influx of calcium into cells, as well as neuroprotective, antineurodegenerative, cognition and memory enhancing, anti-inflammatory, antiviral and many other properties. Chirality plays an important role in the biological activity of 1,4-dihydropyridines. The chemoenzymatic synthesis of 1,4-dihydropyridine derivatives in enantiopure form as the key intermediates for the synthesis of enantiopure drugs and chiral analogues of symmetrical drugs has become an advantageous alternative to the other synthetic methods. Hydrolytic enzymes, as efficient chemo-, regio- and stereoselective biocatalysts have been successfully applied for the asymmetrisation or kinetic resolution of various 1,4-dihydropyridine derivatives. Several synthetic strategies to overcome the inactivity of hydrolytic enzymes towards 1,4-dihydropyridine carboxylic acids have been developed during the last decade, often based on the introduction of a spacer between an enzymatically labile group and the 1,4-DHP nucleus. Good to excellent enantioselectivities can be obtained by careful optimisation of the reaction temperature and the organic (co)solvent used in the enzymatic transformations.     

Chemoenzymatic synthesis of enantiopure 1,4-dihydropyridine derivatives

1,4-Dihydropyridines possess a broad range of biological activities, such as the ability to control the influx of calcium into cells, as well as neuroprotective, antineurodegenerative, cognition and memory enhancing, anti-inflammatory, antiviral and many other properties. Chirality plays an important role in the biological activity of 1,4-dihydropyridines. The chemoenzymatic synthesis of 1,4-dihydropyridine derivatives in enantiopure form as the key intermediates for the synthesis of enantiopure drugs and chiral analogues of symmetrical drugs has become an advantageous alternative to the other synthetic methods. Hydrolytic enzymes, as efficient chemo-, regio- and stereoselective biocatalysts have been successfully applied for the asymmetrisation or kinetic resolution of various 1,4-dihydropyridine derivatives. Several synthetic strategies to overcome the inactivity of hydrolytic enzymes towards 1,4-dihydropyridine carboxylic acids have been developed during the last decade, often based on the introduction of a spacer between an enzymatically labile group and the 1,4-DHP nucleus. Good to excellent enantioselectivities can be obtained by careful optimisation of the reaction temperature and the organic (co)solvent used in the enzymatic transformations.     

Enantiomeric Recognition of Racemic 4‐Aryl‐1,4‐dihydropyridine Derivatives via Chiralpak AD‐H Stationary Phases

The chromatographic chiral resolution of two new series of racemic 4‐substituted‐1,4‐dihydropyridine derivatives was studied on a commercial Chiralpak AD‐H column. Analytes without 5,5‐dimethyl substituents ( 1–15 ) are more efficiently resolved than analytes with 5,5‐dimethyl groups ( 16–30 ). The AD‐H column discriminated between enantiomers through both hydrogen bonding attractions and π–π interactions. This interpretation is in accord with plots of the logarithm of separation factors, log(α), versus σ (Hammett–Swain substituent parameter) and σ⁺ (Brown substituent constant) plots. By elucidating the effects of the remote substituents on these chiral separations, it was shown that the influence of π–π interaction forces increase when steric bulk effects act to decrease the hydrogen bonding attractive forces on the AD‐H column. Chirality 24:854–859, 2012. © 2012 Wiley Periodicals, Inc.     

Antioxidant properties and membranotropic effect of certain derivatives of 1,4-dihydropyridine

Interaction of alpha-tocopherol and 1,4-dihydropyridine with endoplasmic reticulum membranes and model systems, human serum albumin and phospholipid bilayer, was studied using the microcalorimetry and fluorescent probes procedures. Dependence of microviscosity changes in the endoplasmic reticulum membranes on the place of antioxidants localization (protein structures or phospholipid phase) was shown. Increase of membrane structuralization under the influence of 1,4-dihydropyridines blocked their antioxidant action in spontaneous and induced lipid peroxidation.     

Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure–activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC₅₀ value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.     

Plant growth retardant activity of 4-homoisotwistane derivatives

A variety of simple derivatives of 3-substituted 4-homoisotwistane derivatives were prepared, and their effect on the growth of cucumber seedlings in complete darkness was investigated. The 3-hydroxy derivative was found to show a strong inhibitory activity at 50 μg/ml, so a series of other hydroxy derivatives of 4-homoisotwistane, endo-2-, exo-2-, and 5-hydroxy- and exo-2,3-dihydroxy-4-homoisotwistane were prepared in order to obtain information on structure-activity relationships. The endo-2-hydroxy derivative inhibited the growth of cucumber and the germination of lettuce seed at 12.5 μg/ml. All the hydroxy derivatives tested increased the number of adventitious roots in hypocotyls of kidney bean at 100 μg/ml, but they inhibited root formation at the lowest part of the cuttings, and the effect was again exhibited most strongly by the endo-2-hydroxy compound. It is suggested that the 2- and 3-hydroxy derivatives possess a potent activity as plant growth retardants.     

Design,synthesis and molecular docking of 1,4-benzodioxane thiazolidinedione piperazine derivatives as FabH inhibitors

A series of novel 1,4-benzodioxane thiazolidinedione piperazine derivatives targeting FabH were designed and synthesized. The compounds exhibited better inhibitory activity against Gram-negative bacteria by computer-assisted screening, antibacterial activity test and E. coli FabH inhibitory activity test, wherein compound 6j exhibited the most significant inhibitory activity (MIC = 1.80 μΜ for P. aeruginosa, MIC = 1.56 μΜ for E. coli). Besides, compound 6j still showed the best E. coli FabH inhibitory activity (IC₅₀ = 0.06 μΜ). Moreover, the antibacterial activities of all compounds were strongly correlated with the inhibitory ability of FabH, with a correlation coefficient of 0.954. Computational docking studies also showed that compound 6j has interacting with FabH key residues in the active site.     

Design,synthesis and evaluation of 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives as ETA receptor selective antagonists using FRET assay

The endothelin axis and in particular the two receptor subtypes, ET_A and ET_B, are under investigation for the treatment of various diseases such as pulmonary arterial hypertension, fibrosis, renal failure and cancer. Previous work in our lab has shown that 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives exhibit noteworthy endothelin receptor antagonist activity. A series of analogues with modifications centered around position 6 of the heterocyclic quinolone core and replacement of the aryl carboxylic acid group with an isosteric tetrazole ring was designed and synthesized to further optimize the structure activity relationship. The endothelin receptor antagonist activity was determined by in vitro Förster resonance energy transfer (FRET) using GeneBLAzer® assay technology. The most potent member of this series exhibited ET_A receptor antagonist activity in the subnanomolar range with an IC₅₀ value of 0.8 nM, and was 1000-fold selective for the ET_A receptor compared to the ET_B receptor. Its activity and selectivity profile resembles that of the most recently approved drug, macitentan.     

Antioxidant activity of free radical reactions inhibitors, applied to the dressing material for wound healing

Antioxidant activity (AA) of inhibitors of free radical reactions (FRR) (dieton, mexidol, trypsin), applied to the dressing material for wound healing was studied using a model system containing suspension of laminated liposomes, formed from the fraction of total chicken yolk phospholipids. Lipid peroxidation (LPO) of liposome membranes was initiated by addition of Fe²⁺ ions. The kinetics of FRR was monitored by coumarin enhanced chemiluminescence (CL). AA of the inhibitors was determined by their ability to intercept aqueous and hydrophobic free radicals and chelate Fe²⁺ ions. Their ability to intercept radicals reduced in the following order: dieton > trypsin > mexidol. We have also found previously unknown ability of mexidol to interact with Fe²⁺ and to eliminate the FRR catalyst. Studying AA of the FRR inhibitors in the two-components mixture, containing dieton and mexidol, we have observed the multifunctional effect: dieton increased the duration of latent period of CL by intersepting lipid peroxyl radicals, while mexidol, decreased this parameter by interacting with Fe²⁺, i.e. mexidol masked the action of dieton. Study of AA of two-components mixture, containing mexidol and trypsin has demonstrated the same multifunctional effect. In the two-component mixture, containing trypsin and dieton, the inhibitors exhibit synergistic action. All the antioxidant properties of these FRR inhibitors were also preserved in the three component mixture. Thus, the mixture dieton, mexidol and trypsin, possesses high AA, that validates their use in the dressing materials employed for wound healing.     

Free radical scavenging activity of novel thiazolidine‐2,4‐dione derivatives

Free radical activity towards superoxide anion radical (), hydroxyl radical (HO^?) and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH^?) of a series of novel thiazolidine‐2,4‐dione derivatives (TSs) was examined using chemiluminescence, electron paramagnetic resonance (EPR) and EPR spin trapping techniques. 5,5‐Dimethyl‐1‐pyrroline‐N‐oxide (DMPO) was applied as the spin trap. Superoxide radical was produced in the potassium superoxide/18‐crown‐6 ether dissolved in dimethyl sulfoxide. Hydroxyl radical was generated in the Fenton reaction (Fe(II) + H₂O₂. It was found that TSs showed a slight scavenging effect (15–38% reduction at 2.5 mmol/L concentration) of the DPPH radical and a high scavenging effect of (41–88%). The tested compounds showed inhibition of HO^? ‐dependent DMPO‐OH spin adduct formation (the amplitude of EPR signal decrease ranged from 20 to 76% at 2.5 mmol/L concentration. Our findings present new group compounds of relatively high reactivity towards free radicals. Copyright © 2012 John Wiley & Sons, Ltd.     

Lipophilic 1,4-naphthoquinone derivatives: synthesis and redox properties in solution and entrapped in the aqueous cubic liquid-crystalline phase of monoolein

1,4-Naphthoquinone derivatives (NQD) containing lipophilic alkyl chains, i.e. 2-((Z)-heptadec-8-enyl)-3-methyl 1,4-naphthoquinone (QMe), 2-((Z)-heptadec-8-enyl)-3-hydroxy-1,4-naphthoquinone (QOH) and (Z)-octadec-9-enyl 1,4-naphthoquinone-2-carboxylate (QE) were synthesized. The redox behavior of these NQD was studied in ethanol and entrapped in the reversed bicontinuous cubic phase of space group type Pn3m (Q²²⁴) of aqueous monoolein. In ethanol, cyclic voltammetry curves exhibit two pairs of oxidation-reduction peaks arising from the redox processes controlled by adsorption and molecular diffusion. The NQD molecules are also electrochemically active in the cubic phase, indicating the participation in the 2e⁻, 2H⁺-redox cycle at pH < 9. Therefore, it was concluded that the head group of the entrapped NQD reaches the lipid bilayer interface of cubic phase during the process.     

Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan

A new series of Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan (6a–6ae) were synthesized and characterized by ¹H NMR, ESI-MS and elemental analysis. The structure of 6b was further confirmed by single crystal X-ray diffraction. All these novel compounds were screened for their in vitro antioxidant activity employing 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS⁺) and ferric reducing antioxidant power (FRAP) scavenging assays. Due to the combination of 1,4-benzodioxan, 1,3,4-oxadiazoles and substituted phenyl ring, most of them exhibited nice antioxidant activities. In all of these three assays mentioned above, compounds 6f and 6e showed significant radical scavenging ability comparable to the commonly used antioxidants, BHT and Trolox. Seven compounds with representative substituents or activities were selected for further assays in chemical simulation biological systems—inhibition of microsomal lipid peroxidation (LPO) and protection against 2,2′-azobis (2-amidinopropane hydrochloride) (AAPH) induced DNA strand breakage, in which, 6f and 6e were demonstrated to be of the most potent antioxidant activities.     

Studies on the antioxidant activity of some thiazolidinedione,imidazolidinedione and rhodanine derivatives having a flavone core

A series of flavonyl‐2,4‐thiazolidinedione, imidazolidinedione and rhodanine derivatives were tested for their antioxidant activity as scavengers of oxygen free radicals. Free radical scavenging activities, including superoxide anion radical , hydroxyl radical (HO^?) and 2,2′‐diphenyl‐1‐picrylhydrazyl free radical have been evaluated using chemiluminescence, electron paramagnetic resonance and spin trapping with 5,5‐dimethyl‐1‐pyrroline‐1‐oxide as a spin trap. Potassium superoxide in dimethylsulfoxide and 18‐crown‐6 ether were used for the production of . Hydroxyl radical was generated using the Fenton reaction. Ten of the eleven examined compounds exhibited decrease in chemiluminescence, but there were large differences in the decrease, ranging from 16% to 89%; also, two of these compounds increased light emission by about 200%. On the contrary, all compounds tested exhibited 30–68% scavenging HO^? and 25–96% scavenging the DPPH^? radical respectively. Possible mechanisms are proposed to explain the results. Copyright © 2014 John Wiley & Sons, Ltd.     

Antioxidant and neuroprotective effects of synthesized sintenin derivatives

Three series of sintenin derivatives (compounds 1–14) were designed and prepared and their antioxidative and neuroprotective effects were evaluated. The in vitro models of scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, chelating ferrous ions, inhibiting the rat brain homogenates lipid peroxidation, and protecting neurons damaged by hydrogen peroxide were employed for bioassays. It was found that sintenin derivatives 4 and 13 showed remarkable antioxidative and neuroprotective activities.     

Antioxidant activity of resveratrol in endotoxin-stimulated blood platelets

Resveratrol (3,4′,5-trihydroxystilbene) is a natural molecule with antioxidant action. It is also considered to be a molecule with antiplatelet, anticancer and anti-inflammatory action. The effects of trans-resveratrol on the reactive oxygen species (ROS) generation and thiobarbituric acid-reactive substances (TBARS) in blood platelets induced by endotoxin (lipopolysaccharide, LPS) or thrombin were studiedin vitro. The production of superoxide radicals (O₂ ^.–) and other reactive oxygen species (H₂O₂, singlet oxygen, and organic radicals) in the presence of resveratrol was measured by a chemiluminescence method in resting blood platelets and platelets stimulated by LPS (0.3 μg/10⁸ platelets) or thrombin (2.5 U/10⁸ platelets). We have shown that resveratrol (6.25–100 μg/ml) inhibits chemiluminescence and generation of O₂ ^.– in blood platelets. It has an inhibitory effect on the production of ROS and TBARS in platelets caused by LPS or thrombin. This revised version was published online in July 2006 with corrections to the Cover Date.     

The structure-activity relationship study on 2-, 5-, and 6-position of the water soluble 1,4-dihydropyridine derivatives blocking N-type calcium channels

In order to find an injectable and selective N-type calcium channel blocker, we have performed the structure–activity relationship (SAR) study on the 2-, 5-, and 6-position of 1,4-dihydropyridine-3-carboxylate derivative APJ2708 (2), which is a derivative of Cilnidipine and has L/N-type calcium channel dual inhibitory activities. As a consequence of the optimization, 6-dimethylacetal derivative 7 was found to have an effective inhibitory activity against N-type calcium channels with more than 170-fold lower activity for L-type channel compared to that of APJ2708.