Dihydropyridine Derivatives Research Articles

Recent Progresses in the Multicomponent Synthesis of Dihydropyridines by Applying Sustainable Catalysts Under Green Conditions.

The synthesis of dihydropyridines, valuable molecules with diverse therapeutic properties, using eco-friendly heterogeneous catalysts as a green alternative received significant consideration. By selecting appropriate precursors, these compounds can be readily modified to induce the desired properties in the target product. This review focused on synthesising diverse dihydropyridine derivatives in single-pot reactions using magnetic, silica, and zirconium-based heterogeneous catalytic systems. The monograph describes preparation techniques for various catalyst materials in detail. It covers facile and benign magnetic, silica, zirconium-based, and ionic liquid catalysts, exhibiting significant efficacy and consistently facilitating excellent yields in short reaction times and in a cost-effective way. Most of the designated protocols employ Hantzsch reactions involving substituted aldehydes, active methylene compounds, and ammonium acetate. These reactions presumably follow Knoevenagel condensation followed by Michael addition and intra-molecular cyclisation. The multicomponent one-pot protocols using green catalysts and solvents have admirably increased the product selectivity and yields while minimising the reaction time. These sustainable catalyst materials retain their viability for several cycles reducing the expenditure are eco-friendly.

A sustainable molybdenum oxide loaded on zirconia (MoO3/ZrO2) catalysed multicomponent reaction to synthesise novel dihydropyridines

We have synthesised the robust molybdenum oxide supported on zirconium oxide (MoO3/ZrO2) by a simple wet-impregnation method. It proved an effective catalyst for synthesising eleven novel dihydropyridine derivatives in excellent yields (92–96%). The one-pot four-component fusion involved dimethyl-2-amine pyridine, diethyl but-2-ynedioate, various benzaldehydes and malononitrile in ethanol. The swift reactions at room temperature were accomplished in <18 min. The nanocomposite catalyst is stable up to five successive runs with similar catalytic activity. Swift reaction, recyclability, excellent yields, mild conditions, simple workup and column-free protocol are the advantages of this method.

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).

Synthesis and application of [Zr-UiO-66-PDC-SO3H]Cl MOFs to the preparation of dicyanomethylene pyridines via chemical and electrochemical methods

A metal–organic framework (MOF) with sulfonic acid tags as a novel mesoporous catalyst was synthesized. The precursor of Zr-UiO-66-PDC was synthesized both via chemical and electrochemical methods. Then, zirconium-based mesoporous metal–organic framework [Zr-UiO-66-PDC-SO3H]Cl was prepared by reaction of Zr-UiO-66-PDC and SO3HCl. The structure of [Zr-UiO-66-PDC-SO3H]Cl was confirmed by FT-IR, PXRD, FE-SEM, TEM, BET, EDX, and Mapping analysis. This mesoporous [Zr-UiO-66-PDC-SO3H]Cl was successfully applied for the synthesis of dicyanomethylene pyridine derivatives via condensation of various aldehyde, 2-aminoprop-1-ene-1,1,3-tricarbonitrile and malononitrile. At the electrochemical section, a green electrochemical method has successfully employed for rapid synthesis of the zirconium-based mesoporous metal–organic framework UiO-66-PDC at room temperature and atmospheric pressure. The synthesized UiO-66-PDC has a uniform cauliflower-like structure with a 13.5 nm mean pore diameter and 1081.6 m2 g−1 surface area. The described catalyst [Zr-UiO-66-PDC-SO3H]Cl was also employed for the convergent paired electrochemical synthesis of dihydropyridine derivatives as an environmentally friendly technique under constant current at 1.0 mA cm−2 in an undivided cell. The proposed method proceeds with moderate to good yields for the model via a cooperative vinylogous anomeric based oxidation.

AMLODIPINE-INDUCED TESTICULAR DNA DAMAGE AND ITS MODIFICATION BY A HERBAL PREPARATION IN WISTAR ALBINO RATS

The present study originated from the reports of adverse effects on male reproductive potential caused by the dihydropyridine derivative type calcium channel blockers, which are widely used agents for different cardiovascular disorders. The study was conducted to verify whether the repeated administration of this type of calcium channel blockers can cause any testicular DNA damage and if so, whether the damage can be modified by the co-administration of a herbal protective agent. The study was conducted in male Wistar albino rats. The testicular DNA damage of different groups of rats was evaluated by comet assay taking percentage DNA in comet tail as the main parameter. It was found that oral administration of the widely used dihydropyridine type calcium channel blocker amlodipine produced a duration- dependent and significant (P&lt;0.001) DNA damage in the testes of Wistar albino rats. The co- administration of the alcoholic extract of seeds of Asteracantha longifolia produced a dose dependent and significant ((P&lt;0.001) protective effect against this amlodipine-induced testicular DNA damage.

Synthesis and Biological Evaluation of Tetrahydropyrimidine and Dihydropyridine Derivatives Against Leishmania Major.

A number of tetrahydropyrimidines and their bioisosteric dihydropyridines bearing chloro substituent at various positions of phenyl ring in C4 of main scaffolds were designed, synthesized and evaluated for antileishmanial activity. The antileishmanial activity of the synthesized compounds was evaluated against promastigote and amastigote forms. Moreover, molecular docking studies of the compounds in pteridine reductase 1 (PTR1) pocket were carried out to describe the results of biological experiments. The compounds exhibited moderate to good antileishmanial activity against promastigote and amastigote forms. Among the screened compounds, 1d and 2c were found as the most potent compounds against promastigote form with EC50 values of 15.5 and 10.5µM, respectively. Compounds 2a and 2c were the most potent compounds against amastigote form with EC50 values of 5.4 and 2.2µM, respectively. According to structure-activity relationship (SAR) studies, the chloro substituent in different positions of phenyl ring at C4 of 1,2,3,4-tetrahydropyrimidine (THPM) and 1,4-dihydropyridine (DHP) rings and also the length of the chain belonging to the ester groups could be important for antileishmanial activity of these compounds. Most of these compounds exhibited low cytotoxicity against macrophages. Compounds 1h, 2a, 2b and 2c revealed higher activity than glucantime while all compounds showed lower activity toward amphotericine B. Docking studies showed that the synthesized compounds were fit well in the PTR1 pocket. Compounds 1h and 2c indicated the highest score docking among screened compounds in PTR1 enzyme.

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

An innovational validated spectrofluorimetric technique for determination of 6-Aminocaproic acid in pure form and its tablet: Application to spiked human plasma and urine

An innovative and sensitive spectrofluorimetric method has been developed for determination of 6-aminocaproic acid (ACA) in its pure form and its laboratory prepared tablets. The aim of this method is the reaction of ethyl acetoacetate and formaldehyde with the primary amino group presented in ACA as aimed in the Hantzsch reaction, this reaction resulted in formation of a yellow fluorescent dihydropyridine derivative that can be easily detected spectrofluorimetrically at 438 nm (excitation at 358 nm). At the optimum conditions of the reaction, the linear range was found to be (0.7–3.5 µg\\mL) with limit of detection is 0.231 µg\\mL and limit of quantitation is 0.700 µg\\mL. The proposed method used for detection of ACA laboratory prepared tablets with average percentage 100.721 ± 0.701% without any interference from any excipients. This method used for in vitro determination of ACA in spiked human plasma with a percent mean recovery 99.874 ± 1.416%. In addition, the developed method used for determination of ACA in spiked human urine with percent mean recovery 100.314 ± 1.793%.

Application of Hantzsch reaction for sensitive determination of eflornithine in cream, plasma and urine samples.

Eflornithine (EFN) is an anti-Trypanosoma brucei agent for the medication of sleeping sickness and widely distributed for the treatment of hirsutism (unwanted facial hair in women). The presented work demonstrates a comprehensive analytical approach for the spectrofluorometric determination of EFN in commercial cream samples and various biological samples. The proposed method is based on the formation of a highly yellow–green fluorescence dihydropyridine derivative after the interaction between EFN and acetylacetone/formaldehyde reagent in a slightly acidic medium. Furthermore, the optimal variables such as reagent volumes, pH of the medium, heating time, buffer volume, heating temperature and diluting solvent were carefully selected to achieve the maximum fluorescence activity. The fluorescence activity for the formed derivative was measured at λemission = 477 nm after λexcitation = 418 nm. Concerning linearity, accuracy, sensitivity, precision and robustness, the presented method was validated and verified according to ICH guidelines. Moreover, the proposed work offered a selective determination for EFN in various brands of pharmaceutical cream without any interference from excipients. Eventually, the current approach was assured to be successful in the estimation of EFN in urine and plasma samples with acceptable recovery results.

Water Extract of Dragon Fruit Peel Catalyzed Synthesis of Dihydropyridines By Hantzsch Condensation

Nowadays, natural substances are increasingly used in organic synthesis for their safety aspects towards the environment. That is why we identified a natural substance through which it promoted the organic reaction, and it could be sustainable and from plant sources obtained, and through this natural substance, it promotes the synthesis of dihydropyridine and its derivatives under solvent-free conditions. We have resorted to this method, being economical, free of minerals and solvents, to create highly functional dihydropyridine derivatives. It is promoted by the water extract of dragon Fruit (WED) at a temperature of (800C) . these (WED) promoted reactions are found to afford high yield for the desired products and this method is Protocol an alternative to the current procedures.

The first spectrofluorimetric approach for quantification of colistin sulfate and its prodrug colistimethate sodium in pharmaceutical dosage form and human plasma.

A new, accurate, nonextractive, and sensitive fluorimetric approach was proposed and validated for the first time estimation of colistin sulfate and its inactive prodrug colistimethate sodium in its bulk form, pharmaceutical formulations, and human plasma. The approach relied on condensation between acetylacetone/formaldehyde and the primary amino moiety of nonfluorescent colistin in Teorell and Stenhagen buffer (pH 2.8) by the Hantzsch reaction to form a highly fluorescent dihydropyridine derivative. The fluorescent product was measured at 460 nm (λex = 402 nm). A plot of relative fluorescence intensity (RFI) versus concentration was rectilinear over the range 200-4000 ng ml-1 with excellent correlation (r) and determination (r2 ) coefficients of 0.9999 and 0.9998, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were 40.91 and 123.99 ng ml-1 , respectively. The present procedure was useful for determination of colistin sulfate either in powder form for suspension or in its parenteral prodrug colistimethate sodium in vial formulation. The investigated approach was applied for in vitro quantification of this drug in spiked human plasma, with a per cent mean recovery of 98.24 ± 1.34. The proposed method is reliable, selective, and does not require tedious sample pretreatment steps, expensive instrumentation, or harmful reagents, all of which make it ideally suited for use in quality control laboratories.

Dual solvent-catalyst role of deep eutectic solvents in Hantzsch dihydropyridine synthesis

Deep eutectic solvents are a class of new generation green solvents formed from two or more components, which furnish a new homogeneous liquid phase with lower melting point than the individual components. Here, for the first time, dual role of DES as catalyst and reaction medium was studied for the synthesis of symmetric dihydropyridine derivatives from aldehyde, ethyl acetoacetate and ammonium acetate. The present article reports the suitability of six DESs for Hantzsch dihydropyridine synthesis at room temperature. Among this, DES 2 (ZrOCl2.8H2O and ethylene glycol at 1:2 ratio) was found to be the catalyst of choice with excellent recyclability. The role of DES in the present protocol was to activate the reactants through strong hydrogen bonding interaction and provide suitable medium for the reaction. The major advantages of DESs for the titled reaction are the easy preparation, low cost, non-volatility, biodegradability, simple catalytic process, excellent conversion and the reusability.

Boosting the catalytic performance of manganese (III)‐porphyrin complex MnTSPP for facile one‐pot green synthesis of 1,4‐dihydropyridine derivatives under mild conditions

In this study, the metal complex (5,10,15,20‐tetrakis‐(4‐sulfonatophenyl)‐porphyrin manganese (III) chloride; denoted as MnTSPP) represents a promising efficient and reusable heterogeneous solid catalyst for facile and highly efficient one‐pot synthesis of 1,4 dihydropyridine derivatives via three‐component condensation reaction of aromatic aldehyde, ethyl acetoacetate, and ammonium acetate under green and mild reaction conditions. The simple operation, short reaction time (15 min), and the high efficiency (99%) are the special advantage of this protocol. Furthermore, the green aspects of this synthetic protocol were more studied by examination of the reusability of MnTSPP for four consecutive cycles without a significant loss of catalytic activity. Remarkably, the new synthesis presented advantages in terms of safety, commercially available catalyst, simplicity, stability, mild conditions, short reaction time, and excellent yields, using a mixture of H2O and C2H5OH environmental‐friendly solvent, operationally facile, wide tolerance of starting materials, and excellent recoverable of the catalyst.

One-pot synthesis of dihydropyridine carboxylic acids via functionalization of 3-((trimethylsilyl)ethynyl)pyridines and an unusual hydration of alkynes: Molecular docking and antifungal activity

Activation of 3-((trimethylsilyl)ethynyl)pyridine with triflic anhydride followed by nucleophilic addition of bis(trimethylsili) ketene acetals and a unusual alkyne hydration allowed to obtain new series of 3-acetylated dihydropyridine acids 3a-h in a single step. Secondly, docking studies were conducted on four of the test compounds ( 3b , 3e , 17a and 17b ) and a reference drug (fluconazole) at the active site of lanosterol 14α-demethylase enzymes (CYP51) from Candida spp., in vitro inhibition assays were performed with the same compounds and yeast species. Compounds 3b , 3e , 17a and 17b interacted with key amino acids of the active site of CYP51 enzymes in a similar manner as fluconazole. Compared to fluconazole, the test compounds showed better binding energy values (−4.84 to −9.1 vs. −1.51 to 5.68 kcal/mol) and in vitro antifungal activity (lower MIC values) on different Candida species. Hence, the dihydropyridine derivatives can be considered candidates for the development of new antifungal drugs. • Dihydropyridines. • Hydration of alkynes. • Molecular docking. • antifungal activity. • Candida spp.

One‐pot synthesis of 1,4‐dihydropyridine derivatives using the Fe2ZnAl2O7 catalyzed Hantzsch three‐component reaction

AbstractA facile, low‐cost, and effective one‐pot method was developed for the synthesis of 1,4‐dihydropyridine derivatives with high yields through the three‐component reaction of ammonium acetate, ethyl acetoacetate, and aromatic aldehydes using Fe2ZnAl2O7 as catalyst. The reaction was conducted at 70–80°C temperature under solvent free conditions. The developed method had some great advantages, including safe and clean reaction conditions, high to excellent product yields, short reaction time, and a novel and powerful heterogeneous catalyst. The developed heterogeneous solid catalyst had high efficiency and reusability in one‐pot multi‐component syntheses such that it was easily reused four to five times without significant loss in efficiency and product yield. The catalyst was characterized by scanning Electron Microscopy (SEM)/energy‐dispersive X‐ray spectroscopy (EDS) and X‐ray diffraction techniques. N2 sorption isotherms of the prepared nanocomposite exhibited surface area 2.1313E+01 m2/g and total pore volume of 3.0957E‐02 cm3/g. Substituted dihydropyridine derivatives were characterized and confirmed using 1H NMR and 13C NMR, and elemental spectral data.

Nitrite-responsive hydrogel for long-term and smart control of cyanobacteria bloom

Frequent cyanobacteria bloom has caused serious environmental consequences and economic loss, especially in aquaculture. Direct algaecide addition, the most commonly used method, suffered from the poor control and overdose of algaecide. In this manuscript, we designed a smart nitrite-responsive hydrogel (DHPG) loading algaecide (BZK@DHPG) based on selective crosslinker: a kind of dihydropyridine derivatives termed DHPL. The network of the polymer could be decomposed by the nitrite-induced cleavage of DHPL. Compared to the traditional method, BZK@DHPG can adjust releasing speed according to the concentration of NO2−, the marker of cyanobacteria bloom level, and elongate the releasing time. Furthermore, BZK@DHPG could shift the effective dose of algaecide much ahead of the safety threshold, thus reducing deterioration of water quality caused by the overdose of algaecide.

Microwave assisted the short time clean synthesis of 1,3-diketones as building blocks in heterocyclic synthesis: a facile synthesis and antimicrobial evaluation of new dihydropyridine, 4H-pyrane, dihydropyridazine, pyrimidine and pyrazole derivatives

The compounds bearing naphthalene moiety can be used as medical preparations because of their wide spectrum of biological activity and low toxicity. In this study, a new series of azoles or azines were synthesized from the reaction of the key intermediate 1-(1-hydroxynaphthalen-2-yl)-3-phenylpropane-1,3-dione 3 with a variety of electrophilic and nucleophilic reagents under a variety of mild conditions. The chemical structures of these compounds were confirmed by various spectroscopic methods such as (IR, 1H-NMR, 13C-NMR, mass spectra and elemental analyses). The prepared compounds were screened in vitro for their anti-microbial activity against some species of Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeuroginosa). Anti-fungal activities of the compounds were tested against yeast and mycelial fungi,Candida albicans and Aspergillus flavus. The antimicrobial activity of this series was showed either weak or moderate activities.Graphic abstract

A Review: Alternative Methods of Preparing 1, 4- Dihydropyridine Derivatives by Hantzsch Reaction

A Review: Alternative Methods of Preparing 1, 4- Dihydropyridine Derivatives by Hantzsch Reaction

Brønsted acid catalyzed radical addition to quinone methides.

A fundamental quest for alkyl radical generation under mild conditions through photoinduced Brønsted acid catalysis is addressed. The optimized protocol does not require any organic dyes or transition metal photocatalyst. Under blue light irradiation with diphenyl phosphate as a catalyst and dihydropyridine derivatives as a radical source, functionalized arylmethane derivatives are obtained in high yield.

A new convenient methodology based on dihydropyridine derivative for selective fluorimetric analysis of baclofen: Application to spiked urine and content uniformity evaluation

Baclofen belongs to skeletal muscle relaxant and is used for the treatment of muscle spasticity that originated from multiple sclerosis or a spinal cord injury and other cases as hiccups. In the current analytical study, a new, convenient and selective fluorimetric method for baclofen analysis has been developed and validated. The analytical methodology depends on Hantzsch reaction that leads to formation of dihydropyridine fluorescent derivative. The primary amino moiety in baclofen condensed with two equivalents of acetylacetone in the presence of formaldehyde and acetate buffer solutions. Spectrofluorimetric monitoring of the product was accomplished at emission wavelength of 477.3 nm after excitation at 419.9 nm. The method exhibited linearity when baclofen concentration plotted against the fourescence response in the range of 0.3–6.0 µg/mL. Adjustment of the reaction variables and studying validation parameters according to directives of ICH were performed perfectly. Ultimately, the proposed approach was applied successfully for baclofen analysis in raw material, dosage form and spiked urine and it was also extended to test content uniformity.