Modified Hantzsch Reaction Research Articles

Synthesis new fluorinated 4-phenyl-1,4-dihydropyridine derivatives, as perspective antiarrhythmic and antihypertensive drugs

Derivatives of dihydropyridines are promising agents for research, as they have high biological activity. Their low toxicity and polytargeted properties make it possible to create new derivatives and identify new biological activity. As part of this work, we have obtained six new fluorinated derivatives of 4-phenyl-1,4-dihydropyridines. These compounds were synthesized by a modified Hantzsch reaction, the interaction of polyfluorinated sulfur-containing benzaldehydes with ethyl acetoacetate and ethyl 3-aminobut-2-enoate. Studies on the isolated atrium have shown that the possible mechanism of action of the dihydropyridine derivatives lies in the blockade of beta-adrenergic receptors. At the same time, it is not a blocker of potassium and calcium channels. The fluorinated 4-phenyl-1,4-dihydropyridine derivatives, with SCF2H (decrease pressure) and SO2CH3 (increase pressure) groups showed pronounced activity in the study of these derivatives on the blood pressure of rats.

Dehydrogenation of ethanol over CuO–Mg–Y for cross-aldol condensation with aryl aldehydes

An economically viable approach for the synthesis of different α, β-unsaturated aldehydes through modified cross-aldol condensation reaction has been developed. In this synthetic process, acetaldehyde is generated in situ through the catalytic dehydrogenation of the ethanol. The dehydrogenation reaction is found to occur over copper oxide nanoparticles supported on magnesium exchanged zeolite-Y. The formation of acetaldehyde through dehydrogenation of ethanol is confirmed by the modified Hantzsch reaction. Different kinetic studies have been performed to predict the rate of acetaldehyde as well as cinnamaldehyde formation. The formation of α, β-unsaturated aldehydes through the dehydrogenative cross-aldol reaction of ethanol with various aldehydes are found to be dependent on different reaction parameters viz temperature, catalyst amount, time, and the nature of bases. The catalytic dehydrogenation process is found to occur within 80–100 °C. TDDFT calculations are used to correlate the electronic spectra of Hantzsch reaction product with the experimental one.

Novel HM12, A Selective Inhibitor of L‐/T‐type Calcium Channels, Averts Doxorubicin Cardiotoxicity in Male Wistar Rats

Doxorubicin is a cytotoxic anthracycline anticancer drug that is limited by its cardiotoxic action. This study sought to investigate the cardiopreventive potential of HM12, a 1,4‐dihydropyridine (DHP) derivative (CCB) against doxorubicin induced cardiotoxicity in male Wistar rats. HM12 was synthesized as a DHP‐based hexahydroquinoline derivative (2‐[(2‐methylacryloyl)oxy]ethyl 4‐(3,5‐dibromo‐2‐hydro[1]xyphenyl)‐2,6,6‐trimethyl‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) according to the modified Hantzsch reaction via condensation reactions under microwave irradiation. HM12 structure was confirmed using infrared, proton, and carbon‐13 nuclear magnetic resonance, and mass spectra. The CCB activity was evaluated using whole‐cell patch‐clamp assays. Further, fourty‐eight adult male Wistar rats were divided into eight groups of 6/group and received distilled water saline; doxorubicin (DOX, 20 mg/kg, i.p.), HM12 lower (HM12LD) or upper (HM12UD) dose (5 or 20 mg/kg, p.o.), nifedipine (NFD, 20 mg/kg), and their combinations. All rats were sacrificed 24 h after the last administration and changes in blood pressure (BP), heart rate (HR), biochemical, oxidative stress indices, and heart histology were assessed. DOX cardiotoxicity produced spontaneous increased (p<0.05) BP (baseline 106.5/84 mmHg (day 1) versus 170/173.5 mm/Hg (59.6/72%, day 6) and 173.5/167 mmHg (98.8/69.1%, day 7) with altered HR (baseline 99 beats per minutes versus 167.5 bpm (69.1%, day 7). Also, DOX‐treated rats showed a significant increase in tumor necrosis factor‐α (TNF‐α), c‐reactive protein (CRP), and lactate dehydrogenase (LDH). This was accompanied by an increase (p<0.05) in cardiac malondialdehyde (MDAc) and decreased reduced glutathione (GSHc) levels, and activities of catalase (CATc) and superoxide dismutase (SODc). However, HM12UD + DOX had changes BP (baseline 106.5/96 mmHg (day 1) versus 181/179.5 mmHg (70.1/87%, day 6) versus 135/127 mmHg (26.8/32.3%, day 7) with HR (baseline 93.5 beats per minutes versus 164.5 bpm (75.9%, day 6) to 127 bpm (35.8%, day 7). Also, HM12UD was effective against IL‐6, CRP, LDH but not TNF‐α. Further, HM12UD significantly reversed DOX‐induced MDAc by elevating antioxidants GSHc levels as well as activities of CATc and SODs in the treated animals. Additionally, HM12UD averted histopathological changes observed in the rat heart due to DOX intoxication. Overall, the present study conferred new evidence on the protective effects CCBs, in particular, HM12 on DOX‐induced cardiotoxicity, oxidative stress, tumor biomarkers, and cardiac histological changes in rats.

Theoretical and experimental investigation of 1,4-dihydropyridine-based hexahydroquinoline-3-carboxylates: Photophysics and bovine serum albumin binding studies

In this article, the binding affinity of 1,4-dihydropyridine-based hexahydroquinoline-3-carboxylates with bovine serum albumin (BSA) was studied by electronic spectroscopies, quantum calculations, and molecular docking. These compounds were obtained by the one-pot microwave-assisted method via a modified Hantzsch reaction. The photophysical characterization showed in organic solutions absorption maxima in the UV region, ascribed to spin and symmetry allowed electronic transitions 1π–π*. In addition, they presented a main fluorescence emission in the violet-blue regions (406–445 nm), with a relatively large Stokes shift (54–81 nm), depending on the structure of the compounds. BSA fluorescence quenching experiments based on the intrinsic fluorescence of the Trp residues were successfully applied to these compounds, indicating strong interaction with BSA by a static mechanism. The docking simulations corroborated the strong interaction between the studied compounds and BSA, where the surroundings of Trp213 seemed to be the preferred interaction site for all compounds and were responsible for the fluorescence quenching effects.

Discovery of Michael acceptor containing 1,4-dihydropyridines as first covalent inhibitors of L-/T-type calcium channels

1,4-Dihydropyridines (DHPs) are an important class of blockers targeting different calcium channel subtypes and have great therapeutic value against cardiovascular and neurophysiologic conditions. Here, we present the design of DHP-based hexahydroquinoline derivatives as either selective or covalent inhibitors of calcium channels. These compounds were synthesized via a modified Hantzsch reaction under microwave irradiation and characterized by IR, 1H NMR, 13C NMR and mass spectra. Additionally, the proposed structure of HM12 was resolved by single crystal X-ray analysis. The abilities of the target compounds to block both L- and T-type calcium channels were evaluated by utilizing the whole-cell patch clamp technique. Our results identified covalent inhibitors of calcium channels for the first time, which could be achieved by introducing a Michael acceptor group into the ester side chain of the compounds. The proposed covalent binding between the compounds and the cysteine amino acid (Cys1492) within the DHP binding pocket of L-type calcium channel was supported by docking and pharmacophore analysis as well as a glutathione reactivity assay.

Synthesis of Fused 2Н-Pyridin-2-ones under the Conditions of Multicomponent Hantzsch Reaction

One-pot process was studied between a substituted 4-hydroxy-2Н-pyran-2-one and aromatic aldehydes and ammonium acetate in the conditions of modified Hantzsch reaction in acid environment under thermal and microwave activation. Arylmethylenebis-4-hydroxy-2Н-pyridin-2-ones, hydrochromenopyridinone, and their oxygen-containing heteroanalogs were isolated. A primary condensation was confirmed into bispyran-2-one adducts, and at the use of salicilaldehyde, into pyranochromene with subsequent recyclization of pyranone fragments in pyridinone ones.

Synthesis of fused 1,4-dihydropyridines as potential calcium channel blockers

Abstract Objective The aim of this study was to synthesize ten 1,4-dihydropyridine (DHP) derivatives in which substituted cyclohexane rings were fused to the DHP ring and to determine how different ester groups and the benzoyl substituent introduced in 4-phenyl ring affected their calcium channel blocking activity. Methods A microwave-assisted one-pot method was applied for the synthesis of compound 1–5 according to a modified Hantzsch reaction. The benzoyl moiety was introduced in the 4-phenyl ring of these dihydropyridines by refluxing with benzoyl chloride in acetone in the presence of anhydrous potassium carbonate. Synthesized products were characterized by elemental analysis, IR, 1H-NMR and 13C-NMR spectroscopy. The inhibitory actions of compounds 1–10 on calcium channel blocking activity were tested on isolated rat aorta preparations. Results The obtained pharmacological results showed that although all compounds are potent relaxing agents on isolated rat aorta smooth muscle, introduction of a benzoyloxy substitiuent on the phenyl ring (compound 6–10) decreased the relaxant effect of these compunds. Conclusion The reported 1,4-DHP derivatives have calcium channel blocking activity on rat aorta smooth muscle.

Modified Hantzsch reaction in the presence of chiral organic catalysts

Modified Hantzsch reaction in three- and four-component system in the presence of new chiral organic catalysts was investigated and the advantages of this reaction in three-component system compared to four-component one were demonstrated, the influence of catalysts on the dynamics and stereochemistry of the reaction was elucidated. The enantiomeric excess of the main reaction product was evaluated with HPLC, its structure was proved by X-ray diffraction analysis.

Synthesis, structural characterization and myorelaxant activity of 4-naphthylhexahydroquinoline derivatives containing different ester groups

The present study reports the synthesis, structural characterization and myorelaxant activity evaluation of a series of 16 novel 4-naphthyl-hexahydroquinoline derivatives. The compounds were achieved by one-pot microwave-assisted method via a modified Hantzsch reaction. The structures of the compounds were confirmed by various spectral methods like IR, 1D-2D NMR techniques and mass analysis. X-ray studies of compound 10 provided further evidence for the proposed structure. To evaluate their myorelaxant activities, the Emax and pD2 values of the compounds and nifedipine were determined on isolated rabbit gastric fundus smooth muscle strips. The obtained results indicated that introduction of long chain alkyl groups such as 2-methoxyethyl or 2-(methacryloyloxy)ethyl moiety to the ester group led to the most active compounds.

Microwave-assisted synthesis of condensed 1,4-dihydropyridines as potential calcium channel modulators

This study reports the design, synthesis, and calcium channel modulatory activity evaluation of a series of 14 novel fused 1,4-dihydropyridine derivatives. The molecular design of the compounds was based on modifications of nifedipine, which is a calcium channel blocker. The compounds were achieved by one-pot microwave-assisted reaction of 4,4-dimethyl-1,3-cyclohexanedione, 5-chlorosalicylaldehyde/3,5-dichlorosalicylaldehyde, an appropriate alkyl acetoacetate, and ammonium acetate in ethanol according to a modified Hantzsch reaction. The structures of the compounds were confirmed by spectral methods and elemental analysis. To evaluate their relaxant activities, the maximum relaxant response (E$_{\max})$ and pD$_{2}$ values of the compounds and nifedipine were determined on isolated rat aorta rings. The obtained results indicated that all compounds produced concentration-dependent relaxation on the rings possibly due to the blockade of calcium channels. The E$_{\max}$ values (a measure of efficacy) of five compounds were higher than those of nifedipine.

Synthesis and In vitro P-Glycoprotein Inhibitory Activity of Novel 1,4-Dihydropyridine Derivatives


 Two series of new symmetrical 4-aryl-2,6-dimethyl-3,5-bis-N-(aryl/heteroaryl)-carbamoyl-1,4-dihydropyridines (4a-f) and asymmetrical 4-aryl-2,6-dimethyl-3-N-(aryl/hetero-aryl)-carbamoyl-5-ethyl carboxylate-1,4-dihydro-pyridines (5a-f) have been synthesized by simple, economical and eco-friendly, modified Hantzsch reaction using N-aryl/heteroarylacetoacetamides (3a-c), ethylaceto-acetate (for asymmetric), arylaldehydes and urea in presence of catalytic amounts of LiBr/Iodine and by microwave irradiation methods. The newly synthesized compounds were characterized by physical and spectral data, and evaluated for their possible in vitro MDR reversal activity by everted sac method using verapamil as standard P-gp inhibitor and domperidone as the standard P-gp substrate. Amongst the compounds tested, compound 4f exhibited the highest in vitro P-gp inhibitory activity. It was found to be more potent than the standard verapamil.

Chemoenzymatic preparation of optically active 4-aryl-5-carboxy-6-methyl-3,4-dihydro-2(1H)-pyridone derivatives

A series of racemic 4-aryl-5-(tert-butoxycarbonyl)-6-methyl-3,4-dihydro-2(1H)-pyridones have been prepared by means of a modified Hantzsch reaction using commercially available starting materials. An easy removal of the tert-butyl group of these pyridones and subsequent reaction with cesium carbonate and chloromethyl 2-methylpropanoate provided us suitable substrates (±)-5 to be used in lipase-catalyzed hydrolysis reactions. Lipase B from Candida antarctica (CAL-B) was the most adequate lipase in the hydrolysis of (±)-5. Despite the low enantioselectivity values obtained (E≤12), several optically active pyridone derivatives were finally isolated with high enantiomeric excesses (ee≥91%) and moderate yields.

Microwave-Assisted Synthesis and Spasmolytic Activity of 4-Indolylhexahydroquinoline Derivatives

In the present study a microwave-assisted one-pot method was applied for the synthesis of 18 novel condensed 1,4-dihydropyridines carrying the indole moiety. The compounds were achieved by the reaction of appropriate 1,3-cyclohexanedione, substituted indole carboxaldehyde derivative, alkyl acetoacetate and ammonium acetate in methanol, according to a modified Hantzsch reaction. The structure elucidation of the compounds was carried out by spectral methods including X-ray studies. Their spasmolytic activities through calcium channel blockade were assayed on isolated rat ileum. The obtained results indicated that the introduction of the brom atom on the indole ring altered the mentioned activity positively.

ChemInform Abstract: Discovery of Novel 1,4‐Dihydropyridine‐Based PDE4 Inhibitors.

AbstractA series of novel 1,4‐dihydropyridine derivatives (IV) (30 examples) are synthesized via a modified Hantzsch reaction and evaluated for their inhibitory potencies against phosphodiesterase 4.

ChemInform Abstract: Synthesis and anti‐Avian Influenza Virus (H5N1) Evaluation of Some Novel Nicotinonitriles and Their N‐Acyclic Nucleosides.

AbstractPyridine derivative (IV) is easily synthesized by a four‐component modified Hantzsch reaction and used as key intermediate for the preparation of a series of novel fused pyridine derivatives and some acyclic nucleoside derivatives [cf.

Synthesis and Myorelaxant Activity of Fused 1,4‐Dihydropyridines on Isolated Rabbit Gastric Fundus

Abstract Strategy, Management and Health Policy Preclinical Research In the present study, 25 novel condensed 1,4‐dihydropyridine (DHP) derivatives bearing cyclopentane, cyclohexane, or tetrahydrothiopene ring with a bulky and lipophilic moiety (3‐pyridylmethyl) in the ester group were synthesized via a modified Hantzsch reaction, and their calcium channel modulator activities were assayed on isolated rabbit gastric fundus smooth muscle strips. To evaluate the myorelaxant effects of the compounds, the maximum relaxant response (Emax) and pD 2 values were calculated. The results indicated that all compounds produced concentration‐dependent relaxation and the introduction of five‐ or six‐membered rings to the DHP nucleus and 3‐pyridiylmethyl moiety to the ester group led to potent calcium antagonists.

ChemInform Abstract: Scope and Limitations of a Modified Hantzsch Reaction for the Synthesis of Oxazole‐Dehydroamino Acid Derivatives from Dehydroamino Acid Amides.

AbstractA series of oxazoles (III) is prepared in good yields by a Hantzsch‐type reaction of amides (I) with bromides (II) and a subsequent dehydration of intermediate 4,5‐dihydro‐1,3‐oxazol‐4‐ol derivatives.

Synthesis of Cyclopentapyridine and Thienopyridine Derivatives as Potential Calcium Channel Modulators

In this study, novel condensed 1,4-dihydropyridines bearing cyclopentanone (1-21) or tetrahydrothiophene-1,1-dioxide ring (22-42) with various ester substituents were synthesized via a modified Hantzsch reaction and their calcium channel modulator activities were investigated on isolated rat ileum and rat thoracic aorta. The introduction of a cyclopentanone ring fused to the 1,4-dihydropyridine nucleus and methyl, ethyl and allyl moieties to the ester group led to more active calcium modulators.

ChemInform Abstract: Synthesis of 3,5‐Diaroylpyridines.

AbstractPreviously unknown symmetrical 3,5‐diaroylpyridines (IV) are synthesized according to a modified Hantzsch reaction followed by an oxidation step.

Scope and Limitations of a Modified Hantzsch Reaction for the Synthesis of Oxazole-Dehydroamino Acid Derivatives from Dehydroamino Acid Amides

Scope and Limitations of a Modified Hantzsch Reaction for the Synthesis of Oxazole-Dehydroamino Acid Derivatives from Dehydroamino Acid Amides