Malononitrile Derivatives Research Articles

Design, Synthesis, and Bioactivity Determination of Novel Malononitrile Derivatives Containing 1,2,3-Triazole.

Using antifungal agrochemicals as the most economical solution might reduce plant diseases caused by pathogenic fungi, which have a significant negative impact on the quality and yield of food worldwide. In this work, 33 compounds (G) containing 1,2,3-triazole and malononitrile structures were synthesized. When the compounds were tested in vitro against six fungal species, they exhibited significant fungicidal activity toward Botrytis cinerea and Rhizoctonia solani. Compounds G17 and G30 displayed promising in vivo efficacy, with an EC50 of 0.19 and 0.27 mg/L respectively against R. solani. Fungal ergosterol production was suppressed by compounds G17 and G30, according to a preliminary analysis of their mechanism of action on R. solani using transcriptomics and scanning electron microscopy. It has been shown through experimentation that compounds G17 and G30 prevent R. solani from synthesizing ergosterol. Ultimately, it was anticipated that compounds G17 and G30 would be discovered to be low-toxic.

Synthesis, structural, spectroscopic and theoretical insights into a new malononitrile derivative: A candidate for nonlinear optical applications

Functionalized alkylidene malononitriles play a crucial role as donor-acceptor molecules, exhibiting notable nonlinear optical (NLO) properties. Allylidene malononitriles, an analogue of alkylidene malononitriles, have not been explored before for their optical properties. The present work deals with the synthesis of (Z)-2-(3-(4-bromophenyl)-3-chloroallylidene) malononitrile using Knoevenagel condensation reaction of Z-3-(4-bromophenyl)-3-chloroacrylaldehyde and malononitrile. Structure of the compound was elucidated by single-crystal X-ray crystallography and related spectroscopic studies like FT-IR, NMR (1H, 13C), and UV–Vis spectroscopy, which were further supported with computational studies using Density Functional Theory (DFT) approach. The photoluminescence spectra showed that the compound exhibited an emission peak at 425 nm with an excitation wavelength of 352 nm. The single crystal study reveals that the compound belongs to a monoclinic system with space group P21/c. The thermal characteristics of the compound was analysed using TGA-DTA/DSC. Investigation of the third-order nonlinear susceptibility was done by femtosecond Z-scan technique and demonstrated the potential of phenyl-substituted allylidene malononitriles for its nonlinear optical applications. The observed positive lensing and strong reverse saturable absorption (RSA) at both visible (532 nm) and Near IR (800 nm) regions make this compound a promising candidate for optoelectronic applications.

An oxidizer-resistant fluorescence probe for detecting bisulfite and viscosity in biosystems

Fluorescence probes bearing malononitrile derivatives as electron withdrawing group have attracted the interests of many researchers during the past decades. Even for the similar fluorophore, the sensing mechanism and pathway could be much different and hard to predict. Thus, we designed a fluorescence probe consisting 2-(3,5,5-trimethylcyclohex-2-en-1-ylidene)malononitrile as the electron withdrawing group and thienocoumarin as fluorophore in order to investigate the possible superiority in designing related optical sensors. In our research, it is interesting to find that our probe has the different properties compared with the similar reported probe bearing the coumarin fluorophore. The novel fluorescent probe (CSO–CN) was demonstrated to be able to detect HSO3− ions and changes in viscosity with a good resistance to oxidizers. The probe offers high sensitivity (LOD = 0.149 μM) for detecting HSO3− via the Michael addition reaction. It also enables fluorescence emission at 483 nm and the tracking of viscosity alternation by impeding the twisted intramolecular charge transfer (TICT) mechanism. Besides, the dual-functional probe has effectively been utilized to monitor HSO3− level in living cells, zebrafish and real food samples.

Crystal Structures, Molecular Docking and In Vitro Investigations of Two 4-Substituted 2-(5,5-dimethyl-3-styrylcyclohex-2-enylidene)malononitrile Derivatives as Potential Topoisomerase II Inhibitors

Type II topoisomerases (TOP2s) play a key role in altering the DNA topology by transiently cleaving both strands of a DNA duplex. Therefore, increased TOP2 activity is associated with many cancers. Herein, we present the synthesis, structural characterization, virtual screening, and structural exploration, as well as evaluation of the antiproliferative effects of two new 4-substituted 2-(5,5-dimethyl-3-styrylcyclohex-2-enylidene)malononitrile derivatives with potential application in the drug design of isoform-specific TOP2 inhibitors. Both compounds 1 and 2 were verified by ESI-TOF-MS, NMR, and single-crystal X-ray diffraction (SCXRD) analysis. Furthermore, we applied our recently proposed SCXRD/HYdrogen DEsolvation (HYDE) technology platform in order to perform molecular modeling, virtual screening, and structural exploration with 1 and 2. For this purpose, we used the crystal structure of human TOP2β complexed to DNA and the anticancer drug etoposide. Moreover, we further evaluated the antiproliferative activity of 1 and 2 on human hepatocarcinoma HepG2 cells and compared the observed effects with those of the reference hTOP2β inhibitor etoposide. Based on the obtained results, compounds 1 and 2 showed a virtually higher binding affinity (Ki HYDE values) over etoposide towards hTOP2β but lower antiproliferative activity compared to those of etoposide.

An insight into structural, spectroscopic and nonlinear optical Application of a promising malononitrile derivative: (Z)-2-(3-chloro-3-(4-chlorophenyl)allylidene)malononitrile

Conjugated organic single crystals play a pivotal role as donor-acceptor molecules, showcasing nonlinear optical properties due to their unique molecular structure. In the present study, a novel functionalised allylidene malononitrile derivative, (Z)-2-(3-chloro-3-(4-chlorophenyl)allylidene)malononitrile, was synthesised and subjected to various spectroscopic and structural analyses for its optical and structural characterisation. This compound serves as an essential building block in developing photonic and optoelectronic materials. We synthesised the compound through a Vilsmeier-Haack reaction followed by a Knoevenagel condensation reaction and crystallised it using a slow evaporation method. In addition to SCXRD, the structural analysis of the compound was performed using NMR (1H, 13C), mass spectroscopy and FT-IR spectroscopy. The Intermolecular interactions were studied using Hirshfeld surfaces. The optical properties were analysed using UV–visible and photoluminescence spectroscopy. The third-order nonlinearity of the grown crystal was estimated using the NLO coefficients via the widely recognised femtosecond Z-scan technique, equipped with Ti:sapphire-based laser oscillator using laser pulses of 90 fs and a wavelength of 500 nm at various incident powers. It was observed that with increasing laser power, the nonlinear absorption coefficient of the sample also increased. These findings, combined with the calculation of the nonlinear refractive index, conclusively establish the potential of (Z)-2-(3-chloro-3-(4-chlorophenyl)allylidene)malononitrile for optoelectronic applications.

Electrochemical Oxidative Cross-Coupling for the Construction of C(sp3)–C(sp3) Bonds

AbstractA highly effective oxidation cross-coupling method involving para-cresol derivatives and malononitrile derivatives has been developed utilizing undivided electrolytic conditions. This electrochemical approach offers a robust route for synthesizing diverse malononitrile derivatives featuring quaternary carbon centers and incorporating para-phenol groups. Notably, the direct electrooxidation of the C(sp3)–H bond in the para-cresol derivative plays a crucial role in this process under electrolytic conditions. Various para-cresol derivatives and malononitrile derivatives with different substituents are readily compatible with this electrochemical transformation, affording coupling compounds in up to 99% yield.

In vitro inhibition potency of malononitrile derivatives on the activity of two pentose phosphate pathway enzymes: accompanied by molecular docking evaluation.

Many disorders, including cancer and malaria, could be targeted via the pentose phosphate pathway (PPP),whose products are key in biosynthetic reactions incells. The goal of this study was to find new PPP inhibitors. The inhibition effects of malononitrile derivatives on Glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) were analyzed through invitro experiments. Besides, molecular docking studies were performed to predict the interactions having role in inhibition of compounds. K i constants of derivatives were found between 4.24±0.46-69.63±7.75 µM for G6PD and 1.91±0.12-95.07±11.08 µM for 6PGD. Derivatives indicated non-competitive inhibition on both enzymes except forcompound 4. The findings of the molecular docking studies revealed that free-binding energy estimations agreed with invitro data. The structure of these malononitrile derivatives may guide for drug discovery in targeting the PPP.

One-pot photoenzymatic synthesis of β-chiral malononitrile derivatives

Here, we reported a one-pot two-stage photoenzymatic synthesis route to prepare β-chiral malononitrile derivatives with mild reaction conditions and excellent enantioselectivity.

Blue-light-triggered C[sbnd]C bond formation for synthesis of functional malononitrile using CBr4 as photocatalyst

Compounds with cyclic structures derived from malononitrile are crucial in the field of pharmaceutics. Herein, we developed a facile synthetic protocol to give functional malononitrile derivatives via light-triggered alkylation using CBr4 as a photocatalyst under mild and eco-friendly conditions. A rich array of ethylene malononitriles, together with tetrahydrofuran were used as substrates, and metal-free coupling reaction occurred by forming new CC bonds. This reaction showed a wide range of scopes with tolerance of various functional groups with reasonable yields. Mechanism studies with the assistance of DFT calculations indicated such a reaction undertaking a radical pathway. We expected this protocol to be a useful platform for metal-free CC coupling reactions.

An indole–based near–infrared fluorescent “Turn–On” probe for H2O2: Selective detection and ultrasensitive imaging of zebrafish gallbladder

Fluorescent probes play essential roles in medical imaging, where the researchers can select one of many molecules to use to help monitor the status of living systems under investigation. To date, a few scaffolds that allow the in vivo detection of H2O2 are available only. Herein, we provide a highly sensitive and selective near-infrared fluorescent probe that detects H2O2 based on the ICT sensing mechanism. We report the first indole–incorporated fluorescent probe Indo–H2O2 that allows H2O2 detection with a LOD of 25.2 nM featuring a boronate group conjugated to an indole scaffold; the boronate cleaves upon reaction with H2O2. A 5-membered malononitrile derivative was incorporated; Indo–H2O2 has near-infrared (NIR) properties and the reaction time is low (∼25 min) compared to other related probes. Indo–H2O2 was successfully employed in both endogenous and exogenous imaging trials of H2O2 in living cells. Indo–H2O2 also allows the real-time monitoring of H2O2in vivo. It preferentially accesses the gallbladder of zebrafish. Our findings support Indo–H2O2 as a highly sensitive fluorescent NIR probe for detecting H2O2, and an idea to incorporate a central indole unit in future fluorescent probe designs.

Synthesis and Characterization of Some New Pyridine-Carboxamide Derivatives of Potential Biological Activities

A facile synthetic routes to access some new heterocyclic systems containing potent pharmacophoric groups such as pyrazole, pyrazolo[5,1-c]-1,2,4-triazine, 1,2,4-triazino[4,3-a]benzimidazole, and pyridine moieties linked to pyridine-carboxamide moiety are reported. Construction of the target compounds was achieved via reaction of 3-oxo-butanamides 1a,b with hydrazonoyl halides, heterocyclic diazonium salts, and malononitrile derivatives, respectively. The structures of the new products were confirmed by all possible spectral and elemental analyses. The antibacterial assessment showed that one product was moderately active against both K. pneumonia and S. aureus.

Meerwein Arylation of Aryl(alkyl)idenemalononitriles and Diazonium Salts for the Synthesis of 2-(Aryl(alkyl)/arylmethylene)malononitrile Derivatives.

A metal-free Meerwein arylation reaction from aryl(alkyl)idenemalononitriles and diazonium salts for the synthesis of 2-(aryl(alkyl)/arylmethylene)malononitrile derivatives under mild conditions was well developed. Different from the general addition reactions between alkenes and diazonium salts, this study performed the traditional coupling reaction for the formation of C(sp2)-C(sp2) bond arylation products. The radical reaction mechanism was well verified in the control experiments. The other advantages of the approach are broad-scope substrates and good group tolerance. Moreover, the obtained products can be readily converted into high-value asymmetric ketones and hydrogenation reactions.

A convenient synthesis of functionalized trifluoromethylated 2-((isoxazolyl)(aryl)methyl)malononitrile derivatives via one-pot MCRs

An efficient one-pot, three-component reaction for synthesis of trifluoromethylated isoxazolone-tethered trisubstituted methane derivatives was developed by one-pot three-component reaction of 3-(trifluoromethyl)isoxazol-5(4H)-one, malononitrile and aldehydes in the presence of a catalytic amount of triethylamine. Both aliphatic and aromatic aldehydes bearing different functional groups are well tolerated. This work represents the first example of employing 3-(trifluoromethyl)isoxazol-5(4H)-one as one component in MCRs pattern. The structures of new compounds were determined by spectroscopic methods. In addition, a possible mechanism of the reaction was proposed.

Multicomponent synthesis of functionalized 2-amino-4<i>H</i>-pyrans initiated by the Knoevenagel reaction

The multicomponent condensation of aldehydes, malononitrile derivatives, 1,3-dicarbonyl compounds of the carbo- and heterocyclic series, and alkyl halides has been studied. The transformation is initiated by the Knoevenagel reaction and leads to the formation of functionally substituted condensed 2-amino- 4 H-pyrans. The structure of a number of products was studied by X-ray diffraction.

Fast-Specific Fluorescent Probes to Visualize Norepinephrine Signaling Pathways and Its Flux in the Epileptic Mice Brain.

Norepinephrine (NE) is synthesized in the locus coeruleus and widely projected throughout the brain and spinal cord. It regulates various actions and consciousness linked to a variety of neurological diseases. A "hunting-shooting" strategy was proposed in this work to improve the specificity and response rate of an NE fluorescent probe: 2-(cyclohex-2-en-1-ylidene)malononitrile derivatives were chosen as a fluorophore. To create a dual-site probe, an aldehyde group was added to the ortho of the ester group (or benzene sulfonate). Because of its excellent electrophilic activity, the aldehyde group could rapidly "hunt" the amino group and then form an intramolecular five-membered ring via the nucleophilic reaction with the β-hydroxyl group. The -NH- in the five-membered ring "shoots" the adjacent ester group, releasing the fluorophore and allowing for rapid and specific NE detection. The NE release and reuptake ″emetic″-″swallow″ transient process is captured and visualized under the action of the primary NE receptor drug. Furthermore, by introducing halogen into the fluorophore to lengthen the absorption wavelength, improve lipid solubility, and adjust the pKa appropriately, the probe successfully penetrated the blood-brain barrier (BBB). In situ synchronous probe imaging was used to detect the NE level in the brains of epileptic and normal mice, and abnormal expression of NE in the brain was discovered during epilepsy. Brain anatomy was used to examine the distribution and level changes of NE in various brain regions before and after epilepsy. This research provides useful tools and a theoretical foundation for diagnosing and treating central nervous system diseases early.

A one-pot multi-component synthesis of novel 2((1H-Indole-3yl) (Phenyl) methyl) malononitrile derivative by utilizing recoverable and efficient TiO2 nanocatalyst

<p>In this research, we have described a facile and user-friendly protocol for the formation of 2((1H-Indole-3yl)(Phenyl)methyl)malononitrile derivatives using a recoverable and efficient TiO2 nanocatalyst. This protocol is simple and incredibly efficient for the synthesis of novel 2((1H-Indole-3yl)(Phenyl)methyl)malononitrile derivatives. Nanoscale TiO2 is used as the catalyst. Since TiO<sub>2 </sub>has more surface area easily binds with the active site of a reactive molecule and initiates the reaction. At last, TiO<sub>2</sub> also recovered as it acts as a catalyst. This multi-component reaction involves indole, malononitrile, and active aldehyde derivatives in the presence of ethanol as solvent and TiO2 as a nanocatalyst. The synthetic methodology employed for multi-component reactions produces substituted 2((1H-Indole-3yl)(Phenyl) methyl) malononitrile derivatives with an environmentally friendly protocol under modest reaction conditions. This study shows that the recoverable and environmentally friendly TiO2 nanocatalyst is an effective material for the synthesis of 2((1H-Indole-3yl) (Phenyl) methyl) malononitrile derivatives with high yields, rapid reaction at room temperature, and effortless product isolation.</p>

1-Benzamido-1,4-dihydropyridine derivatives as anticancer agents: in vitro and in vivo assays

1,4-Dihydropyridine is a privileged scaffold present in many bioactive molecules, from coenzymes to commercially available drugs. Among other interesting properties, it has been found good anticancer activity in some of these 1,4-DHPs, therefore many research groups are trying to develop new compounds based on this structural core.For this purpose, in this work, a family of 23 new 1,4-dihydropyridines has been synthesized using hydrazide and malononitrile derivatives as precursors. This straightforward catalytic process has given rise to the desired products with moderate to excellent yields. All the compounds have been tested against four different cancer cell lines [HeLa (human cervical carcinoma), Jurkat (leukemia), A549 (human lung cancer) and MIA PaCa-2 (pancreatic cancer)] to establish a preliminary structure–activity relationship. From this study, and among the best candidates, we chose 4-chlorophenyl and 4-(trifluoromethyl)phenyl derivatives in the malononitrile ring to synthesize a second generation of molecules with enhanced cytotoxicity, modifying the substituent in the N-heterocyclic position (acylhydrazine moieties). With this second generation of compounds, we successfully decreased the IC50 until 7 µM.An in-depth analysis of their biological properties suggests that these promising compounds trigger a non-conventional cell death mechanism known as paraptosis. Moreover, the tested photophysical properties of these products show in some cases an interesting long wavelength emission and excitation, potentially leading to new biosensors or theragnostic agents.Finally, in vivo assays concerning the acute toxicity in mice of two of the most active compounds (with an alkyl chain of seven carbon atoms in the acylhydrazine moiety) demonstrated that even dosed at thousands fold the corresponding IC50 values (2500 and 3300 times more concentrated than the IC50 values for the two compounds studied), there was no sign of harmful effects on the tested subjects, results that support their use in further studies to discover new anticancer drugs.

Selectivity of Alkylation of Malononitrile Derivatives with α-Bromocarbonyl Compounds

Selectivity of Alkylation of Malononitrile Derivatives with α-Bromocarbonyl Compounds

DBU Promoted Polysubstituted Arene Formation via a Michael Addition/Cyclization/Elimination Cascade Reaction

The straightforward construction of polysubstituted arenes is essential in both synthetic chemistry and medicinal chemistry. Herein, we reported a DBU promoted Michael addition/cyclization/elimination cascade reaction between vinylogous malononitrile derivatives and chlorinated nitrostyrenes for the synthesis of polysubstituted arenes. The method features mild reaction conditions, wide substrate scope and high yield. Interestingly, preliminary study of the enantioselective version of this cascade was conducted to give chiral biaryl atropisomers with up to 40% ee through center-to-axial chirality transfer strategy.

Organocatalytic Synthesis and DFT Study of Versatile Biologically Active Scaffold of Isatylidene Malononitrile Derivatives

Abstract1,8‐Diazabicyclo[5.4.0]undec‐7‐ene (DBU) efficiently catalyzed the Michael addition reaction of pyridine derivatives with isatylidene malononitrile derivatives to provide adducts in 88 % yield. The electronic and structural properties of the derivatives were estimated using the DFT calculations.