Schiff Base Intermediate Research Articles

Synthesis, Antimicrobial Evaluation, Molecular Docking and Dynamics Simulations of Novel 2,3‐Disubstituted Quinazolin‐4(3H)‐one Derivatives

AbstractThe rise of multidrug‐resistant organisms (MDROs) represents a significant challenge to healthcare, underscoring the need for novel antimicrobial agents. Quinazolinone compounds, noted for their diverse biological activities, particularly at the 2nd and 3rd positions, in conjunction with sulphanilamide and isatin derivatives, present a promising avenue for antibacterial development. This study focuses on the synthesis of novel 2,3‐disubstituted quinazolin‐4(3H)‐one derivatives from Schiff base intermediates GA3A and GA3B. The synthesis involved the reaction of 2‐(substituted phenyl)‐4H‐benzo[d][1,3]‐oxazin‐4‐one with sulphanilamide, and the benzoxazinone intermediates were prepared by reacting anthranilic acid with benzoyl chloride. The antibacterial activities of the Schiff base intermediates and the final Mannich base compounds were evaluated against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa at concentrations of 50 µg/mL and 100 µg/mL using the agar well diffusion method, with Norfloxacin (50 µg/mL) as the reference standard. While all tested compounds exhibited lower antibacterial activity compared to the standard, GA4A1 showed enhanced efficacy against E. coli, achieving the highest docking score of 78.0352 against the E. coli protein (PDB ID: 1KZN). Molecular dynamics simulations revealed that the GA4A1‐E. coli complex stabilized after 40,000 ps, with root mean square deviation (RMSD) values ranging from 2.5 Å to 5 Å and low root mean square fluctuation (RMSF) values between 0.05 Å and 0.2 Å, indicating the stability of the complex. These findings underscore GA4A1’s potential as a potent antimicrobial agent against E. coli.

Syringaldehyde‐DOPO derivative for enhancing flame retardancy and mechanical properties of epoxy resin

AbstractWith the wide application of epoxy resins in adhesives, electronic packaging materials, and aerospace fields, it is necessary to prepare high‐performance flame‐retardant epoxy resins to reduce the fire risk caused by their flammability. In this study, the rigid structure intermediate Schiff base (DMDA‐SH) was synthesized by condensation reaction of syringaldehyde (SH) with O‐Tolidine (DMDA). Then, DMDA‐SH‐DOPO, a novel P/N‐structured biobased flame‐retardant curing agent, was synthesized by addition reaction with 9,10‐dihydro‐9‐oxaza‐10‐phosphame‐10‐oxide (DOPO) and was applied to the preparation of intrinsic flame‐retardant epoxy resin. As expected, DMDA‐SH‐DOPO has good flame‐retardant properties due to the synergistic action of N/P elements. Epoxy resin with only 2.5% DMDA‐SH‐DOPO (P = 0.16%) can pass the UL‐94 V‐0 test. Compared with DGEBA/DDM, DMDA‐SH‐DOPO‐7.5's (P = 0.49%) peak heat release rate was reduced by 48.4% and the limiting oxygen index (LOI) reached 27%, making it a flame‐retardant material. From the point of view of carbonaceous residue performance, the expansion height of carbon residue after DMDA‐SH‐DOPO‐7.5 combustion is significantly increased, and the amount of carbon residue at 800°C is increased by 36.4%. In addition, appropriate DMDA‐SH‐DOPO can effectively improve the bending property of epoxy resin. This study provides a new idea for preparing renewable high‐performance intrinsic flame‐retardant epoxy resin.

Electrochemically Promoted Three-Component Reaction to N-Sulfonyl Amidines.

In this study, a multicomponent reaction via the Mannich intermediate was developed using methanol, secondary amine, and sulfonamide as starting materials. This method uses methanol as a green C1 source. The substrate scope is wide, and the yield is good. The mechanistic study shows that methanol generates formaldehyde under electrochemical conditions, and sulfonyl amidine as a nucleophile reacts with Schiff base intermediates to form N-sulfonyl amidine in a single step.

Picolinaldehyde-Zinc(II)-Palladium(0) Catalytic System for the Asymmetric α-Allylation of N-unprotected Amino Esters.

Reported in this work is a synergistic ternary achiral picolinaldehyde-Zn(II)-chiral palladium complex system for the highly enantioselective α-allylation of N-unprotected amino esters. By utilizing a variety of allylic carbonates or vinyl benzoxazinanones as substrates, α-allyl α-amino esters were obtained in high yields (up to 96%) with high enantioselectivities (up to 98% ee). Control experiments suggest that the coordination of Zn(II) with the Schiff base intermediate enhances the acidity of the α-C-H bonds of amino esters, thereby favoring α-allylation over intrinsic N-allylation. Furthermore, NMR studies reveal an interaction between the chiral palladium complex and the Zn(II)-Schiff base intermediate, leading to the formation of a picolinaldehyde-Zn(II)-Pd(0) catalytic system.

Reactions between pyridoxal and L-amino acids in the absence and in the presence of zinc(II): The role of the metal in the prevention of Pictet-Spengler cyclization

Attempts to obtain Schiff bases from the reactions of pyridoxal with l-histidine and l-tryptophan resulted in Pictet-Spengler cyclization, with formation of potassium 4-[3-hidroxy-5-(methylpyridin-4-yl]-4,5,6,7-tetrahydropyrido[3,4-c]imidazole-6-carboxylate (1) and 1-[2-methyl-3-hydroxy-5-(hydroxymethyl)pyridine-4-yl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2). Investigations on the diastereoselectivity of the reactions by means of NOESY and ROESY bidimensional NMR spectra of 1 and 2 revealed the presence of the cis isomer in both cases. Theoretical calculations of the reactions’ free energies showed that only the formation of the cis isomer of 1 is thermodynamically favored, in accordance with the experimental results. However, the formations of both cis and trans isomers of 2 are thermodynamically favored, suggesting that other factors might have been responsible for the experimental detection of only the cis isomer. One-pot reactions of pyridoxal with l-histidine or l-tryptophan in the presence of zinc acetate or zinc chloride resulted in the formation of [Zn2(Pdx-l-His)2(H2O)2]·4H2O (C1) and [Zn(Pdx-l-Trp)(H2O)]·1.5H2O (C2) complexes in which Pdx-l-His and Pdx-l-Trp are the pyridoxal-l-histidine and pyridoxal-l-tryptophan Schiff bases, respectively, indicating that the metal prevents cyclization upon coordination of the Schiff base intermediate.

Synthesis, Structure Revision, and Anti-inflammatory Activity Investigation of Putative Blumeatin.

Blumeatin, reported herein, bearing two hydroxyl groups at C3' and C5' of ring B, is isolated from the traditional Chinese medicine Blumea balsamifera. But the isolation procedure of blumeatin from plants has limitations of prolonged duration and high cost. A procedure featuring Lewis acid-catalyzed ring closure and chiral resolution via Schiff base intermediates is provided here to prepare optically pure blumeatin and its R-isomer efficiently. Furthermore, the structure revision of putative blumeatin based on a logically synthetic procedure and NMR spectroscopic analysis was conducted. The 1D and 2D NMR data analysis unambiguously confirmed our proposal that the reported blumeatin structure has been misassigned as it corresponds to sterubin, which contains two hydroxyl groups at C3' and C4' of ring B. Finally, the results of the ear-swelling test exhibited that synthetic (±)-blumeatin and (±)-sterubin had moderate anti-inflammatory activity which was less than that of (-)-sterubin.

The SOS response-associated peptidase (SRAP) domain of YedK catalyzes ring opening of abasic sites and reversal of its DNA–protein cross-link

Apurinic/apyrimidinic (AP, or abasic) sites in DNA are one of the most common forms of DNA damage. AP sites are reactive and form cross-links to both proteins and DNA, are prone to strand breakage, and inhibit DNA replication and transcription. The replication-associated AP site repair protein HMCES protects cells from strand breaks, inhibits mutagenic translesion synthesis, and participates in repair of interstrand DNA cross-links derived from AP sites by forming a stable thiazolidine DNA–protein cross-link (DPC) to AP sites in single-stranded DNA (ssDNA). Despite the importance of HMCES to genome maintenance and the evolutionary conservation of its catalytic SRAP (SOS Response Associated Peptidase) domain, the enzymatic mechanisms of DPC formation and resolution are unknown. Using the bacterial homolog YedK, we show that the SRAP domain catalyzes conversion of the AP site to its reactive, ring-opened aldehyde form, and we provide structural evidence for the Schiff base intermediate that forms prior to the more stable thiazolidine. We also report two new activities, whereby SRAP reacts with polyunsaturated aldehydes at DNA 3′-ends generated by bifunctional DNA glycosylases and catalyzes direct reversal of the DPC to regenerate the AP site, the latter of which we observe in both YedK and HMCES-SRAP proteins. Taken together, this work provides insights into possible mechanisms by which HMCES DPCs are resolved in cells.

Low flammability epoxy resin enabled by a phosphaphenanthrene-based oligomer

A structurally novel halogen-free oligomer poly (benzoguanamine phospholipamide) (BQDP) with 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) group and triazine ring was constructed as an effective flame retardant suitable for epoxy resins. BQDP was synthesized successfully via nucleophilic addition reaction between DOPO and intermediate schiff base which was prepared by the condensation reaction of benzoguanamine and terephthalaldehyde. Then, the chemical structure of BQDP was characterized by FTIR and NMR. To determine flame retardant properties and thermal stabilities of the epoxy resin, multiple instruments were performed. BQDP visibly increased the limited oxygen index (LOI) values and UL-94 rating of EP/BQDP samples. Specifically, When EP was incorporated with 5 wt% BQDP (EP-5), the limited oxygen index (LOI) rises from 25.2% to 31.5% and the V-0 rating was reached in UL-94 vertical burning test. BQDP also demonstrated excellent smoke suppression performance, which was inferred from the decreased values of PHRR, THR, TSP and av-EHC, while av-COY and residual mass yields increased by comparing EP and EP/BQDP samples. Furthermore, according to the analyses of SEM, FT-Raman and Py-GC/MS, the results revealed that phosphaphenanthrene combined with triazine exerted the group synergistic effect, then both them played outstanding flame-retardant roles in gaseous and condensed phases.

Characterization of the Oxazinomycin Biosynthetic Pathway Revealing the Key Role of a Nonheme Iron-Dependent Mono-oxygenase.

Oxazinomycin is a C-nucleoside natural product with antibacterial and antitumor activities. In addition to the characteristic C-glycosidic linkage shared with other C-nucleosides, oxazinomycin also features a structurally unusual 1,3-oxazine moiety, the biosynthesis of which had previously been unknown. Herein, complete in vitro reconstitution of the oxazinomycin biosynthetic pathway is described. Construction of the C-glycosidic bond between ribose 5-phosphate and an oxygen-labile pyridine heterocycle is catalyzed by the C-glycosidase OzmB and involves formation of an enzyme-substrate Schiff base intermediate. The DUF4243 family protein OzmD is shown to catalyze oxygen insertion and rearrangement of the pyridine C-nucleoside intermediate to generate the 1,3-oxazine moiety along with the elimination of cyanide. Spectroscopic analysis and mutagenesis studies indicate that OzmD is a novel nonheme iron-dependent enzyme in which the catalytic iron center is likely coordinated by four histidine residues. These results provide the first example of 1,3-oxazine biosynthesis catalyzed by an unprecedented iron-dependent mono-oxygenase.

Synthesis of long chain alkanes via aldol condensation over modified chitosan catalyst and subsequent hydrodeoxygenation

In this paper, jet fuel range alkanes were produced by aldol condensation of furfural and levulinic acid over modified chitosan catalyst and subsequent hydrodeoxygenation. NaOH modified chitosan was developed and used as a solid catalyst in the aldol condensation of furfural and levulinic acid to produce long carbon chain compounds. At room temperature, the total yield of condensation products reached 94.4% over NaOH/CT-4 catalyst. The amine of chitosan plays an important role in the aldol condensation, which reacted with the aldehyde group of the furfural, producing an intermediate Schiff base and promoting the formation of condensation products. This new route avoided the occurrence of side reactions caused by NaOH. Therefore, the yield of the products was greatly increased. Moreover, kinetic analysis of the condensation reaction and the test of catalyst repeatability were also conducted with NaOH/CT-4. The condensation products were further converted to long-chain branched alkanes by hydrodeoxygenation over the 5 wt% Pd/NbOPO4 catalyst. As a potential application, these alkanes could be mixed with and used as the components of jet fuels.

Highly efficient azido-Ugi multicomponent reactions for the synthesis of bioactive tetrazoles bearing sulfonamide scaffolds

Recent studies revealed that the contribution of the different bioactive scaffolds in one structure creates modern drugs/compounds with unique synergistic biological properties. In this regard, thanks to the interesting biological and medicinal properties of sulfonamide and tetrazole skeletons, this study describes the engagement of sulfonamides in the Ugi tetrazole reaction to access a library of tetrazole bearing sulfonamide. This four-component reaction was performed in a one-pot among available starting material, i.e., an isocyanide, a sulfonamide, an aldehyde and sodium azide in MeOH at 45 °C using ZnCl 2 as a catalyst, for the synthesis of very versatile products with high atom economy and yields. The key point in this strategy is the formation of an intermediate Schiff base and its activation in the azido-Ugi reaction by a Lewis acid catalyst. Importantly, all products are purified through the group-assisted purification (GAP) chemistry, which can avoid traditional purification such as recrystallization and chromatography methods. Also, the docking study between the synthesized compounds and human serum albumin (HSA) was stimulated to theoretically rationalize their biological activity and potential binding interactions.

Study on alkylated Schiff base of a triazole with 3, 5-di-tert-butyl-4-hydroxybenzaldehyde as a novel multifunctional lubricant additive

A novel triazole derived multifunctional lube additive (MFA) denoted as TBB was designed and synthesized for improved metal surface interaction properties and inhibiting lubricant degradation. At first, two hindered phenolic moieties were coupled with the heterocyclic 3,5-diamino-1,2,4-triazole framework by the reaction with 3, 5-di-tert-butyl-4-hydroxybenzaldehyde to give the intermediate Schiff base followed by alkylation through the reaction of bromododecane for better solubility in polyol base oil. After molecular characterization, the TBB performance evaluation for the lubricity and antioxidant characteristics was done following the standard test methods in the polyol. At a low concentration of 1000 ppm, the average wear scar diameter and average friction coefficient was reduced by 16.92% and 64.39% respectively while the RBOT time was increased by 70.76% at 5000 ppm concentration with respect to polol base oil. The standard corrosion testing procedures were used for evaluating the anti-corrosion potential of additive TBB in terms of weight loss, corrosion rate, and penetration rate which were found to be reduced at 5000 ppm concentration to the values as 0.01 ± 0.01 mg, 0.01 ± 0.005 mdd, and 0.001 ± 0.001 mpy from the 0.60 ± 0.04 mg, 0.62 ± 0.03 mdd, and 0.114 ± 0.009 mpy respectively for blank polyol. So TBB showed moderate efficiency as a lubricity improver but showed excellent antioxidant and anti-corrosion additive properties.

A facile and durable flame retardant approach for silk fabric through Kabachnik-Fields reaction

This study facilely developed the durable flame retardant (FR) silk fabric by bonding phosphonate groups to silk fiber through Pudovik addition of diethyl phosphite onto Schiff base aldehyde-amine intermediate, namely Kabachnik-Fields reaction. The cross-linking mechanism between FR agent and silk fiber, the thermal resistance, FR ability and durability, and FR mechanism of the modified silk were studied. The modified silk had increased thermal resistance. The modified silk fabric with diethyl phosphite over 13.8 g/L had the self-extinguishing ability and obtained the char length of lower than 11.0 cm and LOI value of higher than 27.4 %, suggesting high FR ability of the modified silk. The modified silk also reached self-extinction after 15 robust launderings, which should be attributed to the covalent cross-linking of phosphonate groups onto silk fiber. The char residue analyses suggested a condensed charring FR mechanism for the modified silk. The Pudovik addition of diethyl phosphite onto silk macromolecular participated Schiff base intermediate shows great possibility to act as effective and durable FR strategy for silk textile.

Structural insights into phosphatidylethanolamine formation in bacterial membrane biogenesis

Phosphatidylethanolamine (PE), a major component of the cellular membrane across all domains of life, is synthesized exclusively by membrane-anchored phosphatidylserine decarboxylase (PSD) in most bacteria. The enzyme undergoes auto-cleavage for activation and utilizes the pyruvoyl moiety to form a Schiff base intermediate with PS to facilitate decarboxylation. However, the structural basis for self-maturation, PS binding, and decarboxylation processes directed by PSD remain unclear. Here, we present X-ray crystal structures of PSD from Escherichia coli, representing an apo form and a PE-bound complex, in which the phospholipid is chemically conjugated to the essential pyruvoyl residue, mimicking the Schiff base intermediate. The high-resolution structures of PE-complexed PSD clearly illustrate extensive hydrophobic interactions with the fatty acyl chains of the phospholipid, providing insights into the broad specificity of the enzyme over a wide range of cellular PS. Furthermore, these structures strongly advocate the unique topology of the enzyme in a lipid bilayer environment, where the enzyme associates with cell membranes in a monotopic fashion via the N-terminal domain composed of three amphipathic helices. Lastly, mutagenesis analyses reveal that E. coli PSD primarily employs D90/D142–H144–S254 to achieve auto-cleavage for the proenzyme maturation, where D90 and D142 act in complementary to each other.

Bioactive fluorenes. Part III: 2,7-dichloro-9H-fluorene-based thiazolidinone and azetidinone analogues as anticancer and antimicrobial against multidrug resistant strains agents

BackgroundThiazoles, thiazolidinones and azetidinones are highly ranked amongst natural and synthetic heterocyclic derivatives due to their great pharmaceutical potential.ResultsNew thiazolidinone and azetidinone class of bioactive agents based on 4-(2,7-dichloro-9H-fluoren-4-yl)thiazole moiety have been successfully synthesized. 4-(2,7-dichloro-9H-fluoren-4-yl)thiazol-2-amine was synthesized and allowed to react with various aryl/heteroaryl aldehydes to afford the corresponding Schiff base intermediates. The target thiazolidinone and azetidinone analogues have derived from Schiff bases by their reactions with thioglycolic acid and chloroacetyl chloride, respectively. The newly synthesized compounds were then evaluated for their antimicrobial activity against some multidrug resistant strains and examined for cytotoxic activity against normal lung fibroblast (WI-38), human lung carcinoma (A549), and human breast carcinoma (MDA-MB-231) cell lines to develop a novel class of fluorene-based bioactive agents. The mode of action and the binding interaction of the synthesized compound with the active sites of dihydrofolate reductase enzyme were well identified by fluorescence-activated cell sorting (FACS) analysis and molecular docking study.ConclusionSome of the synthesized compounds showed remarkable activity against A-549 and MDA-MB-231 when compared to Taxol, which was used as a reference drug. 2,7-dichloro-9H-fluorene-based azetidinones are more efficient as antimicrobial and anticancer agents compared to dichloro-9H-fluorene-based thiazolidinones derivatives.

Synthesis, characterization, and antibacterial activity of N-substituted quaternized chitosan and its cellulose-based composite film

A water and organic soluble N-benzyl-N,N-diethyl quaternized chitosan (NSQC) material was synthesized using chitosan, benzaldehyde, and bromoethane. Amino groups on chitosan reacted with benzaldehyde to form a Schiff base intermediate. Quaternized chitosan was obtained by reacting the Schiff base with bromoethane. The quaternized chitosan was dissolved in an organic solution with dissolved cellulose and cast to prepare quaternized chitosan/cellulose (QCC) film. The molecular structure, morphology, tensile strength, thermal stability, and antibacterial activity effects of NSQC-treated cellulose film were studied in detail. The results showed that the NSQC product exhibited superior solubility in deionized water and dimethylacetamide. The addition of NSQC as a reinforcing agent in QCC film enhanced the interlinking of fibers and slowed down the rate of cellulose pyrolysis, which improved the tensile properties and thermal stability of the cellulose film. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of NSQC showed that it had good antibacterial activity against Staphylococcus aureus and Escherichia coli. The QCC film also showed contact sterilization ability with regards to two kinds of bacteria, which suggested that QCC film has the potential for applications in food packaging and bacterial barriers.

Selective Synthesis of Furfurylamine by Reductive Amination of Furfural over Raney Cobalt

AbstractEffect of metal nature on reductive amination was investigated with biomass‐based furfural as a typical substrate. Among the tested heterogeneous metal catalysts, cobalt proved to be the most effective metal for the synthesis of the corresponding primary amine. Under a relatively mild reaction condition, 98.9 % yield of furfurylamine was obtained over Raney Co and it can be reused more than eight times without a significant decrease in the catalytic performance. By extensively studying the catalytic pathways and reaction mechanism, it is found that the selectivity to primary amine and secondary amine was governed by the relative rate of hydrogenolysis and hydrogenation of the Schiff base intermediate. The superiority of Raney Co in furfurylamine synthesis can be ascribed to its high efficiency on hydrogenolysis of the Schiff base intermediate and its low performance in the hydrogenation of the Schiff base, carbonyl group and furan ring. Furthermore, ammonia greatly promoted the catalytic hydrogenolysis of the Schiff base intermediate over Raney Co without clear deactivation of the metal active sites.

Dual functions of CoOx decoration in PtCo/CeO2 catalysts for the hydrogen-borrowing amination of alcohols to primary amines

Amines, especially primary amines, are value-added fine chemicals widely used in modern industries. Here, a PtCo/CeO2 catalyst is designed for the hydrogen-borrowing amination of alcohols, especially the conversion of cyclopentanol to cyclopentanylamine. CoOx decoration over Pt/CeO2 is able to enhance both selectivity to primary amine and catalytic activity. These CoOx species play two roles in alcohol amination, enhancing alcohol dehydrogenation and inhibiting overhydrogenation of a Schiff base intermediate (cyclopentyl cyclopentylidene amine). Comprehensive characterization demonstrates that promotional effects of the CoOx additive have two causes: (1) CoOx species provide an additional Pt-CoO interface for the rate-determining dehydrogenation step; (2) CoOx species block low-coordinated Pt sites for H2 activation in the overhydrogenation of the Schiff base intermediate, thus suppressing the formation of undesirable secondary amines. This work provides an in-depth understanding of the role of the CoOx additive in PtCo/CeO2 and new insights into the design of Pt-based catalysts for primary amine production via hydrogen-borrowing amination.

Observation and Kinetic Characterization of Transient Schiff Base Intermediates by CEST NMR Spectroscopy.

In aqueous solution, many biochemical reaction pathways involve reaction of an aldehyde with an amine, which progresses through generally unstable, hydrated and dehydrated, Schiff base intermediates that often are unobservable by conventional NMR. There are 4 states in the relevant equilibrium: 1) gem-diol, 2) aldehyde, 3) hemiaminal, and 4) Schiff base. For the reaction between protein amino groups and DOPAL, a highly toxic metabolite of dopamine, the 1 H resonances of both the hemiaminal and the dehydrated Schiff base can be observed by CEST NMR, even when their populations fall below 0.1 %. CEST NMR reveals the quantitative exchange kinetics between reactants and Schiff base intermediates, explaining why the Schiff base NMR signals are rarely observed. The reactivity of DOPAL with Nα -amino groups is greater than with lysine Nϵ -amines and, in the presence of O2 , both types of Schiff base DOPAL-peptide intermediates rapidly react with free DOPAL to irreversibly form dicatechol pyrrole adducts.

Observation and Kinetic Characterization of Transient Schiff Base Intermediates by CEST NMR Spectroscopy

AbstractIn aqueous solution, many biochemical reaction pathways involve reaction of an aldehyde with an amine, which progresses through generally unstable, hydrated and dehydrated, Schiff base intermediates that often are unobservable by conventional NMR. There are 4 states in the relevant equilibrium: 1) gem‐diol, 2) aldehyde, 3) hemiaminal, and 4) Schiff base. For the reaction between protein amino groups and DOPAL, a highly toxic metabolite of dopamine, the 1H resonances of both the hemiaminal and the dehydrated Schiff base can be observed by CEST NMR, even when their populations fall below 0.1 %. CEST NMR reveals the quantitative exchange kinetics between reactants and Schiff base intermediates, explaining why the Schiff base NMR signals are rarely observed. The reactivity of DOPAL with Nα‐amino groups is greater than with lysine Nϵ‐amines and, in the presence of O2, both types of Schiff base DOPAL–peptide intermediates rapidly react with free DOPAL to irreversibly form dicatechol pyrrole adducts.