4-dihydropyridine Derivatives Research Articles

Nanostructured Iron (III)-Copper (II) Binary Oxide as a Highly Efficient Magnetically Recoverable Nanocatalyst for Facile One-pot Synthesis of 2, 4, 5-trisubstituted Imidazole and 1, 4-dihydro Pyridine Derivatives under Solvent-free Conditions

Abstract: The Fe (III)-Cu (II) binary oxide magnetic nanocatalyst emerges as an environmentally friendly and highly efficient solid acid catalyst, demonstrating remarkable utility in the one-pot synthesis of 2, 4, 5-trisubstituted imidazole and 1,4-dihydropyridine compounds, all achieved under solvent-free conditions. A facile co-precipitation method was used to synthesize nanostructured Fe-Cu binary oxide. Notably, this Fe-Cu binary oxide magnetic nanocatalyst proves its eco-friendly credentials as an exceptionally efficient and reusable catalyst, offering ease of handling, recovery, and multiple uses with minimal reactivity loss. Furthermore, the Fe (III)-Cu (II) binary oxide magnetic nanocatalyst's magnetic separability enhances its practicality, allowing for effortless catalyst retrieval after reactions. Significantly, the structural characteristics are meticulously elucidated through advanced analytical techniques, including 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. This work presents a versatile and sustainable solution for catalysis, with wide-reaching implications for green chemistry and the development of reusable, efficient catalysts for organic synthesis. The exceptional performance and eco-friendliness of the Fe-Cu binary oxide magnetic nanocatalyst underscore its practical significance. Fe-Cu binary oxide magnetic nanocatalyst exhibits the highest catalytic activity compared to others. The employment of this catalyst consistently delivers excellent yields in the target reactions, highlighting its potential to contribute positively to sustainable chemical processes.

One-Pot Green Synthesis of 1, 4-Dihydropyridine Derivatives Using Polyindole TiO<sub>2</sub> Nanocatalyst by Solvent Free Method

One-Pot Green Synthesis of 1, 4-Dihydropyridine Derivatives Using Polyindole TiO<sub>2</sub> Nanocatalyst by Solvent Free Method

Recent synthetic and biological aspects of 1, 4-dihydro pyridine derivatives

Among the large variety of organic compounds, heterocycles are interesting compounds widely occurring in nature, showing biological activities. Dihydropyridine (DHP) is a privileged scaffold having nitrogen in a six-membered cyclic ring as a central moiety. DHP is a significant compound studied in medicinal chemistry and pharmacology activities. Therefore, organic chemists have made considerable efforts to create new drug candidates with DHP subunits associated with a known or possible pharmacophore. The Hantzsch is a well-studied synthesis of DHP and pyridines and is currently one of the reliable approaches for preparing various DHP derivatives along with new approaches. The most recent studies on diverse synthesis methods for DHP derivatives during the preceding years were highlighted in this study. The main objective of this review is to discuss various approaches for synthesizing dihydropyridine derivatives and documented rife literature on the different pharmacological applications of these versatile scaffold. The supreme importance is given to 1, 4 DHP in the survey according to their pharmacological activity.

Synthesis of dihydropyrimidinone and dihydropyridine derivatives by a GQDs-based magnetically nanocatalyst under solvent-free conditions

A novel and heterogeneous catalyst were prepared of magnetic nanoparticles Fe3O4 coated with silicate modified with graphene quantum dot-copper (GQD/Cu) and used as an efficient catalyst in the multicomponent reactions of Biginelli and Hantzsch. The nanocatalyst was examined by Fourier Transform Infrared (FTIR), thermogravimetric-differential thermal, X-ray powder diffraction (XRD), vibrating sample magnetometer (VSM), energy‐dispersive X‐ray (EDX), transmission electron microscopy (TEM), and field emission scanning electron microscopy (FESEM) analysis. A wide range of 3, 4-dihydro pyrimidine-2-(1 H)-one (DHPM) and 1, 4-dihydropyridine (DHP) derivatives were synthesized with good-to-excellent efficiencies in the presence of the catalyst using a combination of aldehydes, 1, 3-dicarbonyls, and urea/ammonium acetate. The catalyst was taken out and recovered from the reaction mixture by an external magnetic field and reused after six runs with minimal activity loss.

Rapid, Greener and One-pot Four Component Synthesis of 1, 4-Dihydropyridine Derivatives

In this current research framework, an efficient greener synthesis has been developed for new pyridine derivatives using one-pot four-component reaction. We have synthesized a new series of 1,4-dihydropyridine derivatives in excellent yield via telescopic multicomponent reaction among the aldehyde, malononitrile, anilines and diethyl acetylenedicarboxylate in the presence of piperidine at mild reaction condition without further purification. All the synthesized compounds were characterized by 1H NMR, 13C NMR, FT-IR and mass spectrometry analysis.

A Facile, One-Pot Synthesis of 1,4-Dihydropyridine Derivative by Using Polyaniline Supported Zinc Oxide Nanoparticle via Hantzsch Reaction

Polyaniline-supported zinc oxide nanoparticle is very effective for synthesizing poly-hydro quinoline derivatives in a one-pot multi-component reaction through Hantzsch reaction (4a-l). The green and reusable method is described for a multi-component synthesis of 1, 4-dihydropyridine derivatives via the Hantszch reaction. The heterogeneous nanoparticle was characterized by SEM, XRD, UV, FT-IR, and 1H NMR techniques. The method presented here is developing very simple, environmentally benign, less time and best yield. Also, the catalyst can be recovered as well as reused efficiently.

Full Kinetics and Mechanism Investigation for Generating 4-Substituted 1, 4- Dihydropyridine Derivatives in the Presence of Green Catalyst and Aqueous Medium: Experimental Procedure.

The main objective of the kinetic investigation of the reaction between ethyl acetoacetate 1, ammoniumacetat 2, dimedone 3, and diverse substitutions of benzaldehyde 4-X, (X= H, NO2, CN, CF3, Cl, CH (CH3)2, CH3, OCH3, OCH3, and OH) for generating 4-substituted 1, 4-dihydropyridine derivatives (product 5) was to recognize the most realistic reaction mechanism. The layout of the reaction mechanism was studied kinetically via a UV-visible spectrophotometry approach. Among the various mechanisms, only mechanism1 (path1) involving 12 steps was recognized as a dominant mechanism (path1). Herein, the reactions between 1 and 2 (kobs= 814.04 M-1.min-1) and also between 3 and 4-H (kobs= 151.18 M-1.min-1) can be accepted as the first and second steps (step1 and step2) of the reaction mechanism, respectively. Amongst all steps, only step9 of the dominant mechanism (path1) comprised substituent groups (X) near the reaction center. Para electron-withdrawing or donating groups on the compound 4-X increased the rate of the reaction 4 times more or decreased 8.7 times less than the benzaldehyde alone. So, this step is sensitive for monitoring any small or huge changes in the reaction rate. Accordingly, step9 is the rate-determining step of the reaction mechanism (path1). The recent result is in agreement with the Hammett description of an excellent dual substituent factor (r = 0.990) and positive value of reaction constant (ρ= +0.9502), which confirms that both the resonance and inductive effects "altogether" contribute to the reaction center of step9 in the dominant mechanism (path1).

Fe3O4@cysteine nanocomposite: An efficient and reusable catalyst for the facile, green, one-pot synthesis of 1,4-dihydropyridine via Hantzsch reaction

• Fe 3 O 4 @cysteine magnetic nano particle were prepared. • The catalyst used for Hantzsch reactions for preparing 1, 4-dihydropyridine derivatives with high efficiencies. • Key advantages are high yields, short reaction time and simple work-up procedure. • The nanomagnetic catalyst could be recovered from solution with an external magnet at once, allowing undemanding recovery and reuse. • The catalyst was reused for five times with no considerable decrease in catalytic activity. An efficient, clean, and environmentally friendly three-component/one-pot protocol was developed for the synthesis of 1,4-dihydropyridines using Hantzsch reaction by a reaction of aldehydes, ethyl acetoacetate, and ammonium carbonate using Fe 3 O 4 @cysteine magnetic nanoparticles as a catalyst. This strategy provides several advantages such as good to high yields (79 to 96%), short reaction time, a simple work-up procedure, less tedious workup, mild condition, avoidance of hazardous organic solvents, minimal waste, recyclability of catalyst, ability to tolerate a variety of functional groups which gives economical as well as ecological rewards and no chromatographic purification. The present protocol takes advantage of the fact that water, a green solvent is used in combination with Fe 3 O 4 @cysteine nanoparticles as a catalyst which can be easily recovered magnetically and reused for further runs. Also, this efficient and practical protocol proceeded smoothly in gram scale at lower catalytic concentration. An efficient, clean, and environmentally friendly three-component/one-pot protocol was developed for the synthesis of 1,4-dihydropyridines using Hantzsch reaction by a reaction of aldehydes, ethyl acetoacetate, and ammonium carbonate using Fe 3 O 4 @cysteine magnetic nanoparticles as a catalyst. The advantages of methods are shorter reaction time, milder conditions, easy work-up and purification of products by non-chromatographic methods.

An expeditious one pot green synthesis of novel bioactive 1, 4-dihydropyridine derivatives at ambient temperature and molecular modelling

In the presented synthetic work, a series of novel substituted 1, 4-Dihydropyridine derivatives (DHPs) have been prepared by the reaction of substituted aromatic aldehydes, ethyl acetoacetate, and ammonium acetate in the presence of a heterogeneous catalyst silica sulfuric acid at ambient temperature via expeditious, mild, inexpensive and one pot Hantszch multicomponent synthetic methodology. Various benefits of this approach are simple work-up; short reaction times at ambient reaction temperature, excellent yields, green solvent system, no by-products and purification of products without chromatographic separation. The catalyst was easily recovered by simple filtration and reused up to five times without washing with any solvent and without major loss in its activity. All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR and LC-Mass spectroscopic techniques. Molecular modelling of the synthesized novel compounds with respect to Lipinski rule of five, drug likeness, toxicity profiles, drug score and other physico-chemical properties are described and compared with market available generic drugs. Theoretical screenings data suggested that the reported compounds possessed a broad range of lipophilic character, no toxicity risks and similar bioactivity scores as relative with standard drugs used for comparison.

Dual active 1, 4-dihydropyridine derivatives: Design, green synthesis and in vitro anti-cancer and anti-oxidant studies

The present work describes the design of 1,4-dihydropyridines (1,4-DHPs) with diverse variations in structural and functional groups. The physico-chemical properties and drug-like molecule nature evaluations were carried out using SWISSADME. A simple, economical, eco-friendly, water-mediated and Para-Toluene sulfonic acid catalysed multicomponent and one-pot synthetic method from nitroketene N, S- acetals (NMSM) and corresponding aldehydes has been developed. All compounds (6a-u and 13a-h) were subjected to in vitro assays against two important human cancer cell lines Viz. are Laryngeal carcinoma (Hep2) and Lung adenocarcinoma (A549) cells. The reduction level of DPPH (%) used to evaluate the anti-oxidant properties. The 1,4-DHP derivatives, 6o, 6u and 6l displayed the potent anti-cancer activity with IC50 value of 10 µM, 14 µM and 10 µM against the Hep2 and 8 µM, 9 µM and 50 µM against the A549 cells. Similarly, the anti-oxidant properties of 6o, 6l and 6u at a standard concentration of 50 µg, are found to be 70.12%, 63.90% and 59.57% respectively favours the 1,4-DHP derivatives dual activity potentials. The compounds, 6o and 6l found to be equivalent with standard drug, Doxorubicin.

A Metal Free, Hantzsch Synthesis for Privileged Scaffold 1, 4-Dihydropyridines: A Glycerol Promoted Sustainable Protocol

An eco-compatible, facile and clean strategy for the synthesis of 1, 4-dihydropyridine (1, 4-DHP) derivatives has been reported through one pot multi-component Hantzsch reaction using glycerol as a promoting medium. A nontoxic and cheap by-product of biodiesel industry i.e., glycerol has been utilized as a reaction condition in our protocol. The reported protocol offers a greener, economical and expeditious synthesis of biologically significant 1, 4-DHPs with moderate to excellent yields with high atom economy under metal free mild reaction conditions. In addition, operational simplicity, cost effectiveness, and reusability are the additional advantages of our protocol with the avoidance of hazardous volatile solvents.

SEARCH FOR NOVEL ANTI-FERTILITY AGENT BY MONITORING IN VITRO METABOLIC INHIBITION, CELL MOTILITY AND CELLULAR INTERACTIONS OF NIFEDIPINE ANALOGUES

Current family planning measures predominantly target a female clientele, with relatively few significant developments in male fertility regulation. At present, only effective methods for contraception in men are those that prevent sperm transport, such as condoms and vasectomy. Thus, in an attempt to synthesize non-hormonal, safe, reversible and oral male contraceptive, we have used nifedipine as a prototype molecule. Nifedipine is a calcium channel blocker and popular anti-hypertensive drug. Its reversible anti-fertility effect is a well-known side effect. In order to develop male oral contraceptive, we have synthesized four analogues; m-hydroxy (D5), m-chloro (D6), p-nitro (D7), p-methoxy (D8) aryl 1, 4-dihydropyridine derivative of nifedipine and monitored their effect on sperm motility and metabolic activity. To highlight their mechanism of action on sperm function through membrane interaction, we have studied their molecular level interactions with model membrane using NMR and DSC technique. One of the synthesized analogues (D5) showed promising results.

The cytotoxic effects of VE-3N, a novel 1, 4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms

The cytotoxic effects of VE-3N, a novel 1, 4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms

Synthesis and Anti-Bacterial Activity of 1, 4-Dihydropyridine Derivatives Embedded with Chromone and Dimedone Based Hybrids

Synthesis and Anti-Bacterial Activity of 1, 4-Dihydropyridine Derivatives Embedded with Chromone and Dimedone Based Hybrids

Ultrasound Promoted Catalyst-free Procedure for the Synthesis of 1,4- dihydropyridines and Bi-phenyl Derivatives in Water

Background: A simple and efficient one-pot green synthesis of 1,4-dihydropyridine derivatives and biphenyl derivatives has been reported. The overall conversion was assisted by ultrasound irradiation at ambient temperature (25-30 °C) in aqueous medium. Keywords: Ultrasound irradiation, 1, 4-dihydropyridine derivatives, bi-phenyl derivatives, aqueous reaction medium, catalystfree reaction condition, green approach.

A novel series of 1, 4-Dihydropyridine (DHP) derivatives bearing thiazolidin-4-one: From synthesis to structure

A novel series of 1, 4-Dihydropyridine (DHP) thiazolidin-4-one compounds derived from dihydropyridine hydrazones Schiff bases with thioglycolic acid were synthesized through an efficient Hantzsch reaction and experimentally characterized by spectral methods using IR, 1H NMR, 13C NMR, and mass spectroscopic methods. Herein, DHPs were synthesized by an improved Hantzsch procedure in the excellent yields by three different conditions including reflux condensation, fusion, and the microwave irradiation. An additional comparison of applied methodology routes was used to confirm the advantages including short reaction time, good yields, and operational simplicity. Furthermore, the structural and electronic properties of the studied molecules were theoretically investigated by performing density functional theory (DFT) to access reliable results to the experimental values. The molecular geometry, HOMO, and LUMO of the studied compounds were calculated. The theoretical 13C chemical shift results were also calculated using the gauge independent atomic orbital (GIAO) approach and their respective linear correlations were obtained.

Reduced density gradient as a novel approach for estimating QSAR descriptors, and its application to 1, 4-dihydropyridine derivatives with potential antihypertensive effects.

The relationship between the chemical structure and biological activity (log IC50) of 40 derivatives of 1,4-dihydropyridines (DHPs) was studied using density functional theory (DFT) and multiple linear regression analysis methods. With the aim of improving the quantitative structure-activity relationship (QSAR) model, the reduced density gradient s( r) of the optimized equilibrium geometries was used as a descriptor to include weak non-covalent interactions. The QSAR model highlights the correlation between the log IC50 with highest molecular orbital energy (E HOMO), molecular volume (V), partition coefficient (log P), non-covalent interactions NCI(H4-G) and the dual descriptor [Δf(r)]. The model yielded values of R 2=79.57 and Q 2=69.67 that were validated with the next four internal analytical validations DK=0.076, DQ=-0.006, R P =0.056, and R N=0.000, and the external validation Q 2boot=64.26. The QSAR model found can be used to estimate biological activity with high reliability in new compounds based on a DHP series. Graphical abstract The good correlation between the log IC50 with the NCI (H4-G) estimated by the reduced density gradient approach of the DHP derivatives.

Antihypertensive effects of new dihydropyridine derivatives on phenylephrine-raised blood pressure in rats.

Changes in the substitutions at C-3 and C-5 positions of 4-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine have led to changes in potency of the compounds. The objective of the present study was to examine the hypotensive effects of 5 newly synthesized dihydropyridine derivatives of nifedipine in rats with phenylephrine-raised blood pressure. Anesthetized Sprague-Dawley rats were randomly assigned to 19 groups of 7 animals each. Control group received the vehicle dimethylsulfoxide (0.05 mL), 3 groups were given nifedipine at 100, 300, or 1000 μg/kg, and 5 other groups each composed of 3 subgroups administered one of the 5 new dihydropyridine compound at 100, 300, or 1000 μg/kg. All animals were initially infused with 20 µg/kg/min phenylephrine for 45 min, and were then given a bolus of either dimethylsulfoxide, nifedipine, or new dihydropyridine compounds 20 min after the commencement of phenylephrine infusion. Blood pressure and heart rate (HR) of the animals were measured before and at the end of phenylephrine infusion, or 25 min after injection of vehicle or compounds. Compared to dimethylsulfoxide, nifedipine, and new 1, 4-dihydropyridine derivatives caused significant reductions in MBP. Moreover, cyclohexyl propyl, phenyl butyl, and cyclohexyl methyl analogs of 1, 4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazoyl)-3,5-pyridinedicarboxylase at 100 μg/kg, phenyl butyl, and cyclohexyl methyl analogs at 300 μg/kg, and cyclohexyl methyl analogs at 1000 μg/kg reduced MBP similar to nifedipine. There was no significant difference between HR of all groups before and after administration of the compounds. The findings indicated that changes in substitution at C-3 and C-5 positions of 2-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine were associated with changes in hypotensive activity of the compounds.

Design, Synthesis and Biological Evaluation of New 1, 4-Dihydropyridine (DHP) Derivatives as Selective Cyclooxygenase-2 Inhibitors.

As a continuous research for discovery of new COX-2 inhibitors, chemical synthesis, in vitro biological activity and molecular docking study of a new group of 1, 4-dihydropyridine (DHP) derivatives were presented. Novel synthesized compounds possessing a COX-2 SO2Me pharmacophore at the para position of C-4 phenyl ring, different hydrophobic groups (R1) at C-2 position and alkoxycarbonyl groups (COOR2) at C-3 position of 1, 4-dihydropyridine, displayed selective inhibitory activity against COX-2 isozyme. Among them, compound 5e was identified as the most potent and selective COX-2 inhibitor with IC50 value of 0.30 μM and COX-2 selectivity index of 92. Molecular docking study was performed to determine probable binding models of compound 5e. The study showed that the p-SO2Me-phenyl fragment of 5e inserted inside secondary COX-2 binding site (Arg(513), Phe(518), Gly(519), and His(90)). The structure-activity relationships acquired reveal that compound 5e with methyl and ethoxycarbonyl as R1 and COOR2 substitutions has the necessary geometry to provide selective inhibition of the COX-2 isozyme and it can be a good basis for the development of new hits.

A SIMPLE, EFFICIENT, ONE-POT THREE-COMPONENT DOMINO SYNTHESIS OF HANTZSCH 1,4- DIHYDROPYRIDINE UNDER MILD CONDITIONS

A series of substituted Hantzsch 1, 4-Dihydropyridine derivatives were synthesized and the structures of these compounds were established on the basis of analytical and spectral data such as FT-IR and 1H-NMR. The advantages of this system are one-step procedure, high yields of the products and the ability to carry out large-scale reactions