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A water‐soluble anthraquinone derived from alizarin, 3HAAQ, is introduced as the redox‐active material in a negative potential electrolyte (anolyte) for aqueous redox flow batteries operating at pH 14. The synthesis of 3HAAQ is carried out using the Mannich reaction, which significantly improves the solubility of the new compound, an important factor for its use in RFB. Pairing with potassium ferri/ferrocyanide positive electrolyte, this flow battery exhibits an open‐circuit voltage of 1.24 V and maintains nearly 80% of the theoretical capacity at 40 mA cm−2 current density. [ABSTRACT FROM AUTHOR]

The use of alkylzinc bromides in the multicomponent Mannich reaction is described. Heteroleptic organozinc compounds were obtained in THF or 2-MeTHF by direct insertion of zinc dust into the C–Br bond of alkyl bromides. It was found that the presence of a stoichiometric amount of LiCl was essential for the efficiency of the subsequent three-component coupling with aldehydes and amines. A variety of primary, secondary, and tertiary organozinc reagents as well as secondary amines and aromatic aldehydes could be used for the straightforward preparation of α-branched amines. Interestingly, whereas previously reported work describing the preparation and reaction of organozinc iodides in acetonitrile showed higher reactivity of secondary organozinc reagents over primary ones, reactions in THF in the presence of LiCl led to opposite results, with higher reactivity of primary organozinc reagents.

The synthesis and characterization of two novel diastereomeric Mannich bases was carried out from the reaction of the cyclic aminal (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,70.11,16]icosane 1 and p-cresol 2a and 4-methoxyphenol 2b in a water/dioxane mixture. The title compounds (4a–b) are interesting because bearing two 3-(2-hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl} substituents joined to an arenol ring. The formation of these new Mannich bases in the reaction mixture can be explained by aminomethylation of previously reported di-Mannich base 2,2′-((hexahydro-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(methylene))bis(4-substituentphenol) 3a–b. NMR analysis demonstrated that compounds 4a–b were formed as diastereomeric mixtures. Subsequent experiments revealed that at longer reaction times, the percentage yield of these new products increased considerably (yield percentages up to 22–27%), suggesting a nucleophilic competition between the p-substituted phenols and Mannich bases of type 3 for aminal 1. [ABSTRACT FROM AUTHOR]

The reaction between glycine-type aminonaphthol derivatives substituted with 2- or 1-naphthol and indole or 7-azaindole has been tested. Starting from 2-naphthol as a precursor, the reaction led to the formation of ring-closed products, while in the case of a 1-naphthol-type precursor, the desired biaryl ester was isolated. The synthesis of a bifunctional precursor starting from 5-chloro-8-hydroxyquinoline, morpholine, and ethyl glyoxylate via modified Mannich reaction is reported. The formed Mannich base 10 was subjected to give bioconjugates with indole and 7-azaindole. The effect of the aldehyde component and the amine part of the Mannich base on the synthetic pathway was also investigated. In favor of having a preliminary overview of the structure-activity relationships, the derivatives have been tested on cancer and normal cell lines. In the case of bioconjugate 16, as the most powerful scaffold in the series bearing indole and a 5-chloro-8-hydroxyquinoline skeleton, a potent toxic activity against the resistant Colo320 colon adenocarcinoma cell line was observed. Furthermore, this derivative was selective towards cancer cell lines showing no toxicity on non-tumor fibroblast cells. [ABSTRACT FROM AUTHOR]

An efficient cascade cyclization strategy was developed to synthesize aminobenzofuran spiroindanone and spirobarbituric acid derivatives utilizing 2-bromo-1,3-indandione, 5-bromo-1,3-dimethylbarbituric acid, and ortho-hydroxy α-aminosulfones as substrates. Under the optimized reaction conditions, the corresponding products were obtained with high efficiency, exceeding 95% and 85% yields for the respective derivatives. This protocol demonstrates exceptional substrate versatility and robust scalability up to the Gram scale, establishing a stable platform for the synthesis of 3-aminobenzofuran derivative. The successful synthesis paves the way for further biological evaluations with potential implications in scientific research. [ABSTRACT FROM AUTHOR]

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms. [ABSTRACT FROM AUTHOR]

Hollongdione is the first recorded example of the occurrence of a dammarane hexanor-triterpene in nature possessing antiviral and cytotoxic activity. Its simple one-stage transformation into compounds with terminal alkyne and vinyl chloride fragments via the interaction with phosphorus halides is reported. The copper(I)-catalyzed Mannich reaction of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20(21)-in 3 led to a series of aminomethylated products, while 17-carboxylic acid was obtained by ozone oxidation of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20-chloro-20(21)-en 4; the following direct amidation of the latter has been developed. The structures of all new molecules were established by spectroscopic studies that included 2D NMR correlation methods; the molecular structures of compounds 2–5 were determined by X-ray analysis. [ABSTRACT FROM AUTHOR]

An efficient and practical organocatalyzed asymmetric Mannich/cyclization tandem reaction strategy of 2-benzothiazolimines and 2-isothiocyanato-1-indanones was developed, and novel spirocyclic compounds containing benzothiazolimine and indanone scaffolds were obtained. This chiral thiourea-catalyzed Mannich/cyclization tandem reaction offers chiral spirocyclic compounds with continuous tertiary and quaternary stereocenters in good to high yields (up to 90%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 98% ee) at −18 ◦C. Additionally, the scaled-up synthesis was also performed with retained yield and stereoselectivity, and a reaction mechanism was also proposed. [ABSTRACT FROM AUTHOR]

We offer a new biogenetic proposal for the origin of the complex alkaloid alstonlarsine A, through rearrangement of the Strychnos alkaloids alstolucines B and F. Further, we provide evidence of the chemical feasibility of this proposal in the facile conversion of synthetic alstolucines into alstonlarsine A through a short, efficient sequence of N-methylation, β-elimination, and a cascade 1,7-hydride shift/Mannich cyclization. We believe that this is the first biogenetic proposal involving the tert-amino effect, a hydride-shift-based internal redox trigger of a Mannich cyclization. A further interesting feature of the cascade is that its stereochemical outcome most likely originates in conformational preferences during the hydride shift.

Bacterial infections are the second-leading cause of death, globally. The prevalence of antibacterial resistance has kept the demand strong for the development of new and potent drug candidates. It has been demonstrated that Src protein tyrosine kinases (TKs) play an important role in the regulation of inflammatory responses to tissue injury, which can trigger the onset of several severe diseases. We carried out a search for novel Src protein TK inhibitors, commencing from reported highly potent anti-bacterial compounds obtained using the Mannich reaction, using a combination of e-pharmacophore modeling, virtual screening, ensemble docking, and core hopping. The top-scoring compounds from ligand-based virtual screening were modified using protein structure-based design approaches, and their binding to the Src homology-2 domain of p56lck TK was predicted using ensemble molecular docking. We have prepared a database of 202 small molecules and have identified six novel top hits that can be subjected to further investigation. We have also performed in silico ADMET property prediction for the hit compounds. This combined computer-aided drug design approach can serve as a starting point for identifying novel TK inhibitors that could be further subjected to in vitro studies and validation of antimicrobial activity. [ABSTRACT FROM AUTHOR]

Although the wide variety of bioactivities of curcumin has been reported by researchers, the clinical application of curcumin is still limited due to its poor aqueous solubility. In view of this, a series of dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized (compounds 1–15). Acetate of these derivatives were prepared (compounds 1a–15a). The Mannich reaction and aldol condensation reaction are the main reactions involved in this study. Compounds 6, 10, 12, 3a, 5a, 6a, 7a, 8a, 10a, 11a, 12a, 13a, 14a, and 15a exhibited better in vitro anti-inflammatory activity compared to curcumin in the RAW264.7 cell line. Compounds 5, 1a, 5a, 8a, and 12a exhibited better in vitro antioxidant activity compared to curcumin in the PC 12 cell line. Compounds 11, 13, 5a, 7a, and 13a exhibited better in vitro radiation protection compared to curcumin in the PC 12 cell line. The aqueous solubilities of all the curcumin derivative acetates were greatly improved compared to curcumin. [ABSTRACT FROM AUTHOR]

Marine anti-fouling coatings represent an efficient approach to prevent and control the marine biofouling. However, a significant amount of antifouling agent is added to improve the static antifouling performance of the coatings, which leads to an issue whereby static antifouling performance conflicts with eco-friendly traits. Herein, this work reports an in situ reduction synthesis of silver nanoparticles (AgNPs) within polymers to produce composite coatings, aiming to solve the aforementioned issue. Firstly, urushiol-based benzoxazine monomers were synthesized by the Mannich reaction, using an eco-friendly natural product urushiol and n-octylamine and paraformaldehyde as the reactants. Additionally, AgNPs were obtained through the employment of free radicals formed by phenolic hydroxyl groups in the urushiol-based benzoxazine monomers, achieved by the in situ reduction of silver nitrate in benzoxazine. Then, the urushiol-based benzoxazine/AgNPs composite coatings were prepared by the thermosetting method. AgNPs exhibit broad-spectrum and highly efficient antimicrobial properties, with a low risk to human health and a minimal environmental impact. The composite coating containing a small amount of AgNPs (≤1 wt%) exhibits effective inhibition against various types of bacteria and marine microalgae in static immersion, thereby displaying outstanding antifouling properties. This organic polymer and inorganic nanoparticle composite marine antifouling coating, with its simple preparation method and eco-friendliness, presents an effective solution to the conflict between static antifouling effectiveness and environmental sustainability in marine antifouling coatings. [ABSTRACT FROM AUTHOR]

A robust and practical difluoroalkylation synthon, α,α‐difluoroenol species, which generated in situ from trifluoromethyl diazo compounds and water in the presence of dirhodium complex, is disclosed. As compared to the presynthesized difluoroenoxysilane and in situ formed difluoroenolate under basic conditions, this difluoroenol intermediate displayed versatile reactivity, resulting in dramatically improved enantioselectivity under mild conditions. As demonstrated in catalytic asymmetric aldol reaction and Mannich reactions with ketones or imines in the presence of chiral organocatalysts, quinine‐derived urea, and chiral phosphoric acid (CPA), respectively, this relay catalysis strategy provides an effective platform for applying asymmetric fluorination chemistry. Moreover, this method features a novel 1,2‐difunctionalization process via installation of a carbonyl motif and an alkyl group on two vicinal carbons, which is a complementary protocol to the metal carbene gem‐difunctionalization reaction. [ABSTRACT FROM AUTHOR]

In this study, a series of new carbazole derivatives were studied using several reactions, including the Vilsmeier–Haack reaction. A cyclization reaction within bromoacetic acid was reported to synthesize thiazolidinone compounds, followed by the Mannich reaction by reacting the prepared compound with formaldehyde and secondary amines, that is, diphenylamine, morpholine, and phthalimide. All synthesized compounds were characterized by infrared spectroscopy, liquid chromatography–mass spectrometry, and 1H and 13C nuclear magnetic resonance spectroscopy. The antioxidant activities of all prepared compounds were studied using the free-radical scavenging method using 2,2-diphenyl-1-picrylhydrazyl, demonstrating their moderate activity compared with ascorbic acid as the standard substance. The effectiveness of the prepared compounds as corrosion inhibitors was studied in an acidic medium of sulfuric acid (0.25 mol/L) using the electrochemical method. Acceptable corrosion-inhibition efficiency was achieved, with the highest inhibition rate of 55.21 % for compound VII.

The aminated sodium lignosulfonate (AELS) was prepared through a Mannich reaction and characterized via FT-IR, TG, SEM and XPS in this study. Subsequently, the adsorption capacity of AELS for methyl blue (MB) was evaluated under various conditions such as pH, adsorbent dosage, contact time, initial concentration and temperature. The adsorption kinetics, isotherms and thermodynamics of AELS for methyl blue were investigated and analyzed. The results were found to closely adhere to the pseudo-second-order kinetic model and Langmuir isotherm model, suggesting a single-molecular-layer adsorption process. Notably, the maximum adsorption capacity of AELS for methyl blue (153.42 mg g−1) was achieved under the specified conditions (T = 298 K, MAELS = 0.01 g, pH = 6, VMB = 25 mL, C0 = 300 mg L−1). The adsorption process was determined to be spontaneous and endothermic. Following five adsorption cycles, the adsorption capacity exhibited a minimal reduction from 118.99 mg g−1 to 114.33 mg g−1, indicating good stability. This study contributes to the advancement of utilizing natural resources effectively and sustainably. [ABSTRACT FROM AUTHOR]

Beta-aminocarbonyl compounds are important intermediates produced from Mannich condensation. In this research, benzaldehyde, para-hydroxy acetophenone or para-nitro acetophenone were reacted with a various of primary aromatic amines to give compounds (1-7) and (8-14), respectively. The chemical formulas of the synthesized compounds were confirmed by conducting some physical and spectroscopic measurements, such as, melting points, IR and H1-NMR spectrum. After testing the biological activity of some of the synthesized compounds (8,10,11,13) using Gram-positive (Streptococcus, and Staphylococcus aureus), Gram-negative (Klebsiella spp., and Escherichia coli) bacteria, as well as yeast strains, were chosen for this investigation (candidan albicans). Isolated bacteria were identified using standard methods of isolation and identification, including direct assays and culture on various media. Some theoretical tests have also been carried out such as SwissADME and cardioToxCSM prediction on all prepared compounds to predict their activity in terms of pharmacokinetic properties (ADME) and also predict their cardiotoxicity on some heart functions such as arrhythmia, cardiac failure, heart block, hERG toxicity, Hypertension (HT), and Myocardial Infarction (MI). [ABSTRACT FROM AUTHOR]

Obesity has become a serious global public health risk threatening millions of people. In this study, the astaxanthin–anthocyanin nanoparticles (AXT-ACN NPs) were used to investigate their effects on the lipid accumulation and antioxidative capacity of the high-sugar-diet-induced high-fat Caenorhabditis elegans (C. elegans). It can be found that the lifespan, motility, and reproductive capacity of the high-fat C. elegans were significantly decreased compared to the normal nematodes in the control group. However, treatment of high-fat C. elegans with AXT-ACN NPs resulted in a prolonged lifespan of 35 days, improved motility, and a 22.06% increase in total spawn production of the nematodes. Furthermore, AXT-ACN NPs were found to effectively extend the lifespan of high-fat C. elegans under heat and oxidative stress conditions. Oil-red O staining results also demonstrated that AXT-ACN NPs have a remarkable effect on reducing the fat accumulation in nematodes, compared with pure astaxanthin and anthocyanin nanoparticles. Additionally, AXT-ACN NPs can significantly decrease the accumulation of lipofuscin and the level of reactive oxygen species (ROS). The activities of antioxidant-related enzymes in nematodes were further measured, which revealed that the AXT-ACN NPs could increase the activities of catalase (CAT), superoxidase dismutase (SOD), and glutathione peroxidase (GSH-Px), and decrease the malondialdehyde (MDA) content. The astaxanthin and anthocyanin in AXT-ACN NPs showed sound synergistic antioxidation and lipid-lowering effects, making them potential components in functional foods. [ABSTRACT FROM AUTHOR]

We have designed and synthesized a series of bioinspired pyrano[2,3-f]coumarin-based Calanolide A analogs with anti-HIV activity. The design of these new calanolide analogs involved incorporating nitrogen heterocycles or aromatic groups in lieu of ring C, effectively mimicking and preserving their bioactive properties. Three directions for the synthesis were explored: reaction of 5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one with (i) 1,2,4-triazines, (ii) sulfonylation followed by Suzuki cross-coupling with (het)aryl boronic acids, and (iii) aminomethylation by Mannich reaction. Antiviral assay of the synthesized compounds showed that compound 4 has moderate activity against HIV-1 on enzymes and poor activity on the cell model. A molecular docking study demonstrates a good correlation between in silico and in vitro HIV-1 reverse transcriptase (RT) activity of the compounds when docked to the nonnucleoside RT inhibitor binding site, and alternative binding modes of the considered analogs of Calanolide A were established. [ABSTRACT FROM AUTHOR]

Esters of kynurenic acid, a known neuroprotective agent were reacted with cyclic amino acids to yield novel alkoxymethylated products under optimized reaction conditions. The importance of amino acid based (primary, secondary, biogenic and synthetic) organic additives was proven by the conduction of numerous test reactions. Thoroughly extended investigations, directly focusing on amino acid catalysis, which is an emerging and up-to-date field of catalysis and green chemical processes, have been conducted. The mechanism of the alkoxymethylation reaction was proposed and later the findings supported the hypothesis of the first retro-Mannich step (formation of the ortho-quinone methide intermediate) and subsequent formation of the alkoxymethylated derivatives. As a preparative result, two novel kynurenic acid derivatives bearing an alkoxymethyl moiety and two additional derivatives having amino acid residues at the site C-3 were synthesized, thus setting the scope and limitations of the modified Mannich reaction of kynurenic acid derivatives using amino acid nucleophiles. The mechanistic investigations highlighted the significant physicochemical effects of used nucleophiles on the amino-acid driven one-pot retro-Mannich initiated alkoxylation of kynurenic acid.

An efficient cascade cyclization strategy was developed to synthesize aminobenzofuran spiroindanone and spirobarbituric acid derivatives utilizing 2-bromo-1,3-indandione, 5-bromo-1,3-dimethylbarbituric acid, and ortho-hydroxy α-aminosulfones as substrates. Under the optimized reaction conditions, the corresponding products were obtained with high efficiency, exceeding 95% and 85% yields for the respective derivatives. This protocol demonstrates exceptional substrate versatility and robust scalability up to the Gram scale, establishing a stable platform for the synthesis of 3-aminobenzofuran derivative. The successful synthesis paves the way for further biological evaluations with potential implications in scientific research.

A simple, mild and efficient method was proposed to construct fused tricyclic skeletons based on Mannich reaction. This work not only develops a new method to construct the tricyclic skeletons effectively, but also provides a new insight into the fused tricyclic skeletons containing flexible ring, which will greatly contribute to the research and development of the tricyclic energetic compounds. The relationship of structure-activity was studied by weak interactions calculation, single crystal structures analysis, electrostatic potentials calculation. The experimental and theoretical investigations suggest that the fused tricyclic skeleton containing flexible ring possesses better thermal stability and can be derivatized more easily compared with the similar aromatic fused tricyclic skeleton. Besides, the energetic derivates based on the fused tricyclic skeleton containing flexible ring possess good comprehensive properties: 2 (D ​= ​7726 ​m ​s−1, p ​= ​22.7 ​GPa) and 4 (D ​= ​8151 ​m ​s−1, p ​= ​26.3 ​GPa). All these results suggest that the fused tricyclic skeleton containing flexible ring is an ideal candidate to construct energetic compounds.

This review presents all currently known macroheterocyclic compounds that include a bispidine (3,7-diazabicyclo[3.3.1]nonane) fragment in their structure. A classification of bispidine-containing macroheterocycles, which is based on the ring size and the nature of bispidinic nitrogen atoms, is suggested. Synthetic approaches to the studied compounds are classified and considered. The features of the crystal structures and solution behavior of bispidine macroheterocycles are analyzed. Prospects for the development of these organic receptors are proposed.

The development of advanced sustainable biomedical materials with superior biosafety and bioactivity for clinical applications is highly desirable. In the present investigation, biomass-based nanoparticles (NPs) were assembled through the Mannich reaction between the plant polyphenols and the broad-spectrum antibiotic tigecycline (TG). The fabricated NPs with uniform size demonstrated excellent oxidative balance effects, pH-responsive release properties and antibacterial performances. Furthermore, the intracellular and in vivo studies confirmed that the NPs are capable of reducing oxidative damage to cells and significantly repairing tissue injury in mice with peritonitis. This work presents an effective method and idea for constructing biomass-based materials for the treatment of infection-induced diseases. [ABSTRACT FROM AUTHOR]

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products. [ABSTRACT FROM AUTHOR]

α-Substituted-7-azaindoline amides and α,β-unsaturated 7-azaindoline amides have emerged as new versatile synthons for various metal-catalyzed and organic-catalyzed asymmetric reactions, which have attracted much attention from chemists. In this review, the progress of research on 7-azaindoline amides in the asymmetric aldol reaction, the Mannich reaction, the conjugate addition, the 1,3-dipole cycloaddition, the Michael/aldol cascade reaction, aminomethylation and the Michael addition-initiated ring-closure reaction is discussed. The α-substituted-7-azaindoline amides, as nucleophiles, are classified according to the type of α-substituted group, whereas the α,β-unsaturated 7-azaindoline amides, as electrophiles, are classified according to the type of reaction. [ABSTRACT FROM AUTHOR]

The study focuses on the synthesis of isatin- barbituric acid compounds through a two-step process. In the first step, using mannich reaction, new derivatives of Isatin are synthesized by reacting Isatin with either barbituric acid, along with formaldehyde. This reaction results in the formation of Isatin-barbituric acid derivative. In the second step, these Isatin derivatives are further reacted with various aniline derivatives to generate new compounds containing Isatin. Spectroscopic methods including FTIR, ¹H NMR, and 13C NMR are used to characterize the produced molecules. The study investigates the biological effects of several of the synthetic chemicals on certain bacterial strains, including Klebsiella pneumoniae and Staphylococcus aureus. The potential antibacterial activities of these substances are evaluated. [ABSTRACT FROM AUTHOR]

NO gas therapy is a supplementary approach for tumor treatment due to the advantages of minimal invasion, little drug resistance, low side effect and amplified efficacy. l -Arginine (L-Arg), a natural NO source with good biocompatibility, can release NO under the stimulation of H 2 O 2 in tumor microenvironment. However, the conventional l -Arg delivery systems via noncovalent loading usually lead to inevitable premature leakage of nano-cargos during blood circulation. In this work, an efficient l -Arg self-delivery supramolecular nanodrug (SDSND) for tumor treatment is demonstrated by combining Mannich reaction and π-π stacking. l -Arg links to (-)-epigallocatechin gallate (EGCG) with the assistance of formaldehyde through Mannich reaction, and then assembles into nanometer-sized particles via π-π stacking. The guanidine group of l -Arg and the phenolic hydroxyl groups of EGCG are preserved in the SDSNDs, which allows for accomplishing gas therapy by provoking tumor cell apoptosis and combining with EGCG to amplify apoptosis, respectively. In addition, the SDSNDs exhibit high biocompatibility and avoid the premature leakage of l -Arg in blood circulation, providing an alternative l -Arg delivery system for NO gas therapy. NO gas therapy has attracted emerging interest in tumor treatment. However, the controlled NO release and the avoidance of premature leakage of NO donors remain challenging. In this work, L-Arginine (L-Arg) self-delivery supramolecular nanodrug for efficient tumor therapy is demonstrated through the Mannich reaction of L-Arg, (-)-epigallocatechin gallate (EGCG) and formaldehyde. Stimulated by tumor microenvironment, the guanidine groups of L-Arg allow for accomplishing NO release and thus provoking tumor cell apoptosis. The nanodrug also avoids the premature leakage of L-Arg in blood circulation. Moreover, the preserved phenolic hydroxyl groups of EGCG combine with L-Arg to amplify apoptosis. The nanodrug exhibits high biocompatibility and good therapeutic effect, providing an alternative L-Arg delivery system for NO gas therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Aim. To develop a preparative method for the synthesis of N-trimethylsilylimine of trifluoropyruvate, and study its interaction with acetone under organocatalytic conditions. Results and discussion. A simple preparative approach to the first representative of N-silylimines of trifluoropyruvate was developed based on the interaction of triphenylphosphinimide and trifluoropyruvic acid methyl ester by the aza-Wittig reaction. It was found that the addition of acetone to N-silylimine occurred in the presence of L- or D-proline and led to the formation of enantiomerically enriched α-amino-γ-oxocarboxylates. The hydrolysis of the ester function resulted in (R)-α-trifluoromethyl aminocarboxylic acid, and the cyclocondensation with isocyanates or 2,5-dimethoxytetrahydrofuran yielded nitrogen-containing heterocycles containing pyrimidine or pyrrolizine nuclei. Experimental part. The synthetic procedures for the N-silylimine of trifluoropyruvate and its reaction with acetone are provided, along with the transformations of obtained α-amino-γ-oxocarboxylates (hydrolysis, cyclocondensations with isocyanates and 2,5-dimethoxytetrahydrofuran). The structures of the compounds synthesized were proven by 1H, 13C, 19F NMR spectroscopy methods, as well as by the elemental analysis. Conclusions. A convenient method for the synthesis of N-silylimine of trifluoropyruvate has been developed. Using the example of the Mannich reaction with acetone, it has been demonstrated that N-silylimine of trifluoropyruvate is a convenient substrate for the synthesis of optically active 3,3,3-trifluoroalanine derivatives.

The title compound, C20H21F3N2O4, features a main twelve-membered difuryl ring with which the furan rings make dihedral angles of 76.14 (5) and 33.81 (5)°. The dihedral angle between the furan rings is 42.55 (7)°. The six-membered nitrogen heterocycle has a twist-boat conformation. In the crystal, pairs of molecules are connected by intermolecular C—H...O interactions, generating an R22(14) ring motif. These pairs of molecules form zigzag chains along the a-axis direction by means of C—H...F interactions. Furthermore, C—H...π and C–F...π interactions link the molecules into chains along the b-axis direction, forming sheets parallel to the (001) plane. These sheets are also connected by van der Waals interactions.

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products.

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure−activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies. The Mannich reaction is a well-established method for the synthesis of β-amino carbonyl compounds while the analogous reactions of homo-enol or its equivalents with imines or iminium ions are much less explored. Here, the authors describe a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction. [ABSTRACT FROM AUTHOR]

Diazo compounds are rare natural products possessing various biological activities. Kinamycin and lomaiviticin, two diazo natural products featured by the diazobenzofluorene core, exhibit exceptional potency as chemotherapeutic agents. Despite the extensive studies on their biosynthetic gene clusters and the assembly of their polyketide scaffolds, the formation of the characteristic diazo group remains elusive. l-Glutamylhydrazine was recently shown to be the hydrazine donor in kinamycin biosynthesis, however, the mechanism for the installation of the hydrazine group onto the kinamycin scaffold is still unclear. Here we describe an O-methyltransferase-like protein, AlpH, which is responsible for the hydrazine incorporation in kinamycin biosynthesis. AlpH catalyses a unique SAM-independent coupling of l-glutamylhydrazine and polyketide intermediate via a rare Mannich reaction in polyketide biosynthesis. Our discovery expands the catalytic diversity of O-methyltransferase-like enzymes and lays a strong foundation for the discovery and development of novel diazo natural products through genome mining and synthetic biology. Diazo compounds, such as kinamycin, are rare bioactive natural products whose assembly has been extensively studied, but the formation of the diazo group is elusive. Here, the authors report O-methyltransferase-like protein, AlpH, which is responsible for the l-glutamylhydrazine incorporation in kinamycin biosynthesis. [ABSTRACT FROM AUTHOR]

This review presents all currently known macroheterocyclic compounds that include a bispidine (3,7-diazabicyclo[3.3.1]nonane) fragment in their structure. A classification of bispidine-containing macroheterocycles, which is based on the ring size and the nature of bispidinic nitrogen atoms, is suggested. Synthetic approaches to the studied compounds are classified and considered. The features of the crystal structures and solution behavior of bispidine macroheterocycles are analyzed. Prospects for the development of these organic receptors are proposed. [ABSTRACT FROM AUTHOR]

Using oleanolic acid as a starting compound, a series of new oleanane-type triterpenic derivatives were synthesized via O-acylation (with nicotinic, isonicotinic, and methoxycinnamic acid acyl chlorides), N-amidation (with cyclic- or polyamines), the Mannich reaction (with secondary cyclic amines), and Claisen–Schmidt condensation (with aromatic aldehydes), and their potencies as treatments for immunometabolic disorders were investigated. The compounds were evaluated against α-glucosidase and PTP1B enzymes and LPS-stimulated murine macrophages. It was found that the target compounds are highly effective α-glucosidase inhibitors but lack activity against PTP1B. A leading compound, N-methylpiperazine methylated 2,3-indolo-oleanolic propargyl amide 15, is also a micromolar inhibitor of NO synthesis in LPS-stimulated macrophages and suppresses oxidative bursts in neutrophils with similar efficiency. These results, in addition to its ability to stimulate glucose uptake in rat fibroblasts and improve maltose tolerance in rats, allow us to consider compound 15 a promising prototype drug for the treatment of immunometabolic defects in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aminated lignin (AL) was obtained by modifying technical lignin (TL) with the Mannich reaction, and aminated lignin-based titanate nanotubes (AL-TiNTs) were successfully prepared based on the AL by a facile hydrothermal synthesis method. The characterization of AL-TiNTs showed that a Ti–O bond was introduced into the AL, and the layered and nanotubular structure was formed in the fabrication of the nanotubes. Results showed that the specific surface area increased significantly from 5.9 m2/g (TL) to 188.51 m2/g (AL-TiNTs), indicating the successful modification of TL. The AL-TiNTs quickly adsorbed 86.22% of Cr(VI) in 10 min, with 99.80% removal efficiency after equilibration. Under visible light, AL-TiNTs adsorbed and reduced Cr(VI) in one step, the Cr(III) production rate was 29.76%, and the amount of total chromium (Cr) removal by AL-TiNTs was 90.0 mg/g. AL-TiNTs showed excellent adsorption capacities of Zn2+ (63.78 mg/g), Cd2+ (59.20 mg/g), and Cu2+ (66.35 mg/g). After four cycles, the adsorption capacity of AL-TiNTs still exceeded 40 mg/g. AL-TiNTs showed a high Cr(VI) removal efficiency of 95.86% in simulated wastewater, suggesting a promising practical application in heavy metal removal from wastewater. [ABSTRACT FROM AUTHOR]

The title compound, systematic name 4,4',6,6'-tetrachloro-2,2'-{[(2-methoxy-ethyl)azanediyl]bis(methylene)}diphenol (C17H17Cl4NO, 1), was prepared via a modified Mannich reaction between 2-meth-oxy-ethyl-amine, 2,4-dichlorophenol, and aqueous formaldehyde. The resulting amine bis(phenol) provides an interesting comparison to related species as a result of the electron-withdrawing substituents on the phenol rings, in combination with similar steric parameters. One of the Cl atoms was modeled as a two-component disorder with partial occupancies of 0.49 (3) and 0.51 (3), while the pendant ether group was modeled as a two-component disorder with partial occupancies of 0.867 (3) and 0.133 (3). A comparison of metrical parameters for the title compound and closely related structures provides insight into the use of these species as ligands to support transition-metal complexes for applications as homogeneous catalysts. [ABSTRACT FROM AUTHOR]

A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from 4-(3-chlorophenyl)-5-(3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione and different piperazine derivatives. The structures of the products were confirmed by 1H and 13C NMR and elemental analysis. The activity of piperazine derivatives against bacteria (Gram-positive: Staphylococcus epidermidis, Staphylococcus aureus, Micrococcus luteus, Bacillus cereus, and Bacillus subtilis; Gram-negative: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Proteus mirabilis) and yeasts (Candida glabrata, Candida krusei, and Candida parapsilosis) was determined by the minimum inhibitory concentration and minimum bactericidal concentration values. Significant activity was observed against Gram-positive bacteria, mainly staphylococci (PG7–PG8) and bacteria of the genes of Micrococcus and Bacillus (PG1-3), as well as selected strains of Gram-negative bacteria, including bacteria of the Enterobacteriaceae family (PG7), while all tested compounds showed high fungistatic activity against Candida spp. yeasts, especially C. parapsilosis, with MICs ranging from 0.49 µg/mL (PG7) to 0.98 µg/mL (PG8) and 62.5 µg/mL (PG1-3). In conclusion, the results obtained confirm the multidirectional antimicrobial activity of the newly synthesized piperazine derivatives. Furthermore, in silico studies suggest that the tested compounds are likely to have good oral bioavailability. The results obtained will provide valuable data for further research into this interesting group of compounds. The library of compounds obtained is still the subject of pharmacological research aimed at finding new interesting biologically active compounds. [ABSTRACT FROM AUTHOR]

The proposed article relates to synthesis and the study of new propargyl ester derivatives, and biostimulation activity of 4-(bis(2- hydroxyethyl)amino)but-2-yn-1-yl butyrate. Aminomethylation reactions of the obtained propargyl ester with ethanolamine and paraform were carried out in the presence of a catalyst. Copper salts were used as a catalyst. The structure of the new propargyl ester derivatives was established by IR and ¹H-, 13C- NMR spectroscopy. Comparative tests show that the test derivative of the drug 4-(bis(2- hydroxyethyl)amino)but-2-yn-1-yl butyrate showed a higher growth-promoting activity. [ABSTRACT FROM AUTHOR]

Obesity is a global public health concern brought on by a combination of excessive dietary intake, inactivity and genetic predisposition. Pyridopyrimidines have received considerable interest in the development of obesity and diabetes. Mannich reaction was applied on 2-thioxo-pyridopyrimidinone derivative with a variety of aromatic and heterocyclic aromatic amines and formaldehyde by grinding at 25°C in the presence of HCl to obtain 18 fused thiadiazinones and two bis-fused thiadiazinone derivatives. Additionally, in silico docking was performed to investigate the mode of actions of the 20 synthesized compounds against fat mass and obesity-associated (FTO) protein. The ligand molecules are nicely docked to the target FTO with binding energies (ΔGbind) ranging from −11.6 to −8.0 kcal/mol. Electrostatic potential map of semiempirical optimized compound 16 was performed using Gaussian 03. Interestingly, two bis-fused thiadiazinone derivatives showed marked amelioration of adiposity in the high-fat diet model especially in hepatic and adipose tissues.

Co-hydrothermal carbonization (co-HTC) of N-rich and lignocellulosic biomass is a potential way to produce hydrochar with high yield and quality, but the nitrogen will also enrich in a solid product. In this study, a novel co-HTC with acid–alcohol assistance is proposed, and the model compounds bovine serum albumin (BSA) and lignin were used to investigate the role of the acid–alcohol-enhanced Mannich reaction in nitrogen migration. The results showed that the acid–alcohol mixture could inhibit nitrogen enrichment in solids and the order of the denitrification rate was acetic acid > oxalic acid > citric acid. Acetic acid promoted solid-N hydrolysis to NH4+ while oxalic acid preferred to convert it to oil-N. More tertiary amines and phenols were generated with oxalic acid–ethanol addition and then formed quaternary-N and N-containing aromatic compounds through the Mannich reaction. In the citric acid–ethanol–water solution, NH4+ and amino acids were captured to form diazoxide derivatives in oil and pyrroles in solids through both nucleophilic substitution and the Mannich reaction. The results are able to guide biomass hydrochar production with the targeted regulation of nitrogen content and species. [ABSTRACT FROM AUTHOR]

In the current study, the conjugate of 3-oxo-lithocholic acid with N-methylpiperazine and paraform was synthesized using the Mannich reaction and evaluated for antiviral activity. This modification resulted in a dramatic increase of antiviral activity combined with a two-fold decrease of toxicity. Together, these effects led to a strong increase of selectivity of compound (SI = 40 vs. 3 for 3 and 2, correspondingly). [ABSTRACT FROM AUTHOR]

Currently, 1-amidoalkyl-2-naphthol derivatives are of increasing interest due to their biological activities and further use in the preparation of other important bioactive molecules, such as aminoalkyl naphthols and oxazines. The synthesis of 1-amidoalkyl-2-naphthol moiety is usually achieved by employing one-pot multicomponent Mannich reactions. This review covers the recent reports on 1-amidoalkyl-2-naphthols' preparation with the use of different catalysts and summarizes the available published data for the period of the last 3 years. It also puts emphasis on the structure, synthetic transformation and biological importance of this class of products. [ABSTRACT FROM AUTHOR]

Sclareolide was developed as an efficient C-nucleophilic reagent for an asymmetric Mannich addition reaction with a series of N-tert-butylsulfinyl aldimines. The Mannich reaction was carried out under mild conditions, affording the corresponding aminoalkyl sclareolide derivatives with up to 98% yield and 98:2:0:0 diastereoselectivity. Furthermore, the reaction could be performed on a gram scale without any reduction in yield and diastereoselectivity. Additionally, deprotection of the obtained Mannich addition products to give the target sclareolide derivatives bearing a free N-H group was demonstrated. In addition, target compounds 4–6 were subjected to an antifungal assay in vitro, which showed considerable antifungal activity against forest pathogenic fungi. [ABSTRACT FROM AUTHOR]

8-hydroxyquinoline (oxine) is a widely known and frequently used chelating agent, and the pharmacological effects of the core molecule and its derivatives have been studied since the 19th century. There are several synthetic methods to modify this core. The Mannich reaction is one of the most easily implementable examples, which requires mild reaction conditions and simple chemical reagents. The three components of the Mannich reaction are a primary or secondary amine, an aldehyde and a compound having a hydrogen with pronounced activity. In the modified Mannich reaction, naphthol or a nitrogen-containing naphthol analogue (e.g., 8-hydroxyquinoline) is utilised as the active hydrogen provider compound, thus affording the formation of aminoalkylated products. The amine component can be ammonia and primary or secondary amines. The aldehyde component is highly variable, including aliphatic and aromatic aldehydes. Based on the pharmacological relevance of aminomethylated 8-hydroxyquinolines, this review summarises their syntheses via the modified Mannich reaction starting from 8-hydroxyquinoline, formaldehyde and various amines. [ABSTRACT FROM AUTHOR]

Methacrolein (MAL) is an important intermediate extensively used in the manufacture of methyl methacrylate and other materials (polymers and resins). In this study, a series of secondary amines/acids were explored as catalysts for the condensation of formaldehyde and propionaldehyde to prepare MAL. It was found that the structure of the amines and acids directly affected the yield of MAL. The effect of the catalyst was closely related to the nucleophilicity of the amines as well as the steric hindrance effect, while acids also played a role as co-catalysts. Dibutylamine acetate was selected as the catalyst after investigation. The catalytic performance of the system was systematically studied by a series of single-factor experiments, including stirring rate, temperature, reaction time, acid/amine ratio, and the solvent, and the optimized reaction conditions were obtained. In the optimum condition, the yield of MAL was up to 97.3%. Kinetic experiments were performed for the condensation of formaldehyde and propionaldehyde to MAL, and the activation energies, reaction orders, and rate-limiting step of the reaction were determined. The results indicate that the decomposition of the Mannich base is a rate-limiting step. [ABSTRACT FROM AUTHOR]

The application of lignin-based adsorbents in the efficient removal of phosphate from wastewater has attracted much attention and been intensively studied in recent years. However, most currently reported lignin-based adsorbents are difficult to recover and recycle. Herein, we have developed a recyclable, nanostructured bio-adsorbent, poly(ethyleneimine) (PEI)-modified lignin (LG) integrated with Fe3O4 and Zr-La dual-metal hydroxide (LG-NH2@Fe3O4@Zr-La), by the Mannich reaction followed by the chemical coprecipitation method. Multilayer adsorption existed on the surface of LG-NH2@Fe3O4@Zr-La based on the isotherm fitting curve, and its adsorption capacity reached 57.8 mg P g−1, exhibiting a higher phosphate uptake than most reported metallic oxide-based composites. The adsorption process was dominated by inner-sphere complexation of ligand-exchange and electrostatic interactions. Moreover, LG-NH2@Fe3O4@Zr-La exhibited excellent selectivity against coexisting anions, and the adsorption was more efficient under acidic conditions. When the phosphate concentration was 2.0 mg P L−1, the removal efficiency of phosphate reached 99.5% and the residual concentration was only 10 μg P L−1, which meets the United States Environmental Protection Agency (USEPA) standard for eutrophication prevention. In addition, the LG-NH2@Fe3O4@Zr-La displayed excellent reusability, maintaining 91.8% of removal efficiency after five cycles. Importantly, owing to the magnetic properties of the loaded Fe3O4, the resulting composite could be separated within 30 s under an external magnetic field. Thus, the separable and recyclable biobased magnetic adsorbent developed in this work exhibited promising application in phosphate capture from real sewage. This research study provides a new perspective for lignin valorization in lignocellulose biorefineries and establishes an approach for developing an economical and efficient bio-adsorbent for phosphate removal from wastewater. [ABSTRACT FROM AUTHOR]

We have designed and synthesized a series of bioinspired pyrano[2,3-f]coumarin-based Calanolide A analogs with anti-HIV activity. The design of these new calanolide analogs involved incorporating nitrogen heterocycles or aromatic groups in lieu of ring C, effectively mimicking and preserving their bioactive properties. Three directions for the synthesis were explored: reaction of 5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one with (i) 1,2,4-triazines, (ii) sulfonylation followed by Suzuki cross-coupling with (het)aryl boronic acids, and (iii) aminomethylation by Mannich reaction. Antiviral assay of the synthesized compounds showed that compound 4 has moderate activity against HIV-1 on enzymes and poor activity on the cell model. A molecular docking study demonstrates a good correlation between in silico and in vitro HIV-1 reverse transcriptase (RT) activity of the compounds when docked to the nonnucleoside RT inhibitor binding site, and alternative binding modes of the considered analogs of Calanolide A were established.

In the current study, the conjugate of 3-oxo-lithocholic acid with N-methylpiperazine and paraform was synthesized using the Mannich reaction and evaluated for antiviral activity. This modification resulted in a dramatic increase of antiviral activity combined with a two-fold decrease of toxicity. Together, these effects led to a strong increase of selectivity of compound (SI = 40 vs. 3 for 3 and 2, correspondingly).

Candida albicans are highly widespread pathogenic fungi in humans. Moreover, its developed biofilm causes serious clinical problems, leading to drug failure caused by its inherent drug tolerance. Hence, the inhibition of biofilm formation and virulence characteristics provide other means of addressing infections. Polymer composites (PCs) derived from natural products have attracted increasing interest in the scientific community, including antimicrobial applications. PCs are a good alternative approach to solving this challenge because of their excellent penetration power inside biofilms. The main objectives of this study were to synthesize a novel curcumin-based polybenzoxazine polymer composite (poly(Cu-A) PC) using Mannich condensation reaction and evaluate their potency as an antibiofilm and anticorrosive candidate against C. albicans. In addition, their anticorrosive efficacy was also explored. PC exhibited significant antibiofilm efficacy versus C. albicans DAY185 by the morphologic changing of yeast to hyphae, and>90% anticorrosive efficacy was observed at a higher dose of PC. These prepared PC were safe in vivo against Caenorhabditis elegans and Raphanus raphanistrum. The study shows that a polybenzoxazine polymer composite has the potential for controlling biofilm-associated fungal infections and virulence by C. albicans, and opens a new avenue for designing PCs as antifungal, anticorrosive agents for biofilm-associated fungal infections and industrial remediation. [ABSTRACT FROM AUTHOR]

This study describes the preparation of a lignin-based expandable flame retardant (Lignin-N-DOPO) using grafting melamine and covering 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) using the Mannich reaction. Then, through in situ growth, a metal-organic framework (MOF) HKUST-1 (e.g., Cu3(BTC)2, BTC = benzene-1,3,5-tricarboxylate)/lignin-based expandable flame retardant (F-lignin@HKUST-1) was created. Before that, lignin epoxy resin containing phosphorus (P) and nitrogen (N) components had been created by combining epoxy resin (EP) with F-lignin@HKUST-1. Thermogravimetric analysis was used to examine the thermal characteristics of epoxy resin (EP) composite. The findings indicate that the thermal stability of EP is significantly affected by the presence of F-lignin@HKUST-1. Last but not least, the activation energy (E) of EP/15% F-lignin@HKUST-1 was examined using four different techniques, including the Kissinger-SY iteration method, the Ozawa-SY iteration method, the Lee-Beck approximation-iteration method, and the Gorbatchev approximation-iteration method. It was discovered that the activation energy was significantly higher than that of lignin. Higher activation energy suggests that F-lignin@HKUST-1 pyrolysis requires more energy from the environment, which will be significant about the application of lignin-based flame retardants. [ABSTRACT FROM AUTHOR]