Synthesis and antibacterial activity of methylated N-(4-N,N-dimethylaminocinnamyl) chitosan chloride

The methylated chitosan containing different aromatic moieties were synthesized by two steps, the reductive amination and the methylation. The chemical structures of all methylated derivatives, methylated N-(4-N,N-dimethylaminocinnamyl) chitosan chloride (MDMCMCh), methylated N-(4-pyridylmethyl) chitosan chloride (MPyMeCh), and N,N,N-trimethyl chitosan chloride (TMChC) were characterized by ATR-FTIR and ¹H NMR spectroscopy. The molecular weights of the methylated chitosan derivatives were determined by gel permeation chromatography. The results revealed that the molecular weights of chitosan and N-aryl chitosan derivatives could be reduced by the methylation process. The degree of N-substitution (DS) and the degree of quaternization (DQ) were calculated by ¹H NMR ranged from 50% to 76%, and 28% to 82%, respectively. The water solubility of the methylated chitosan derivatives decreased with increasing concentration and pH. The antibacterial studies of these methylated chitosan derivatives were carried out by using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods against Escherichia coli ATCC 25922 (Gram-negative) and Staphylococcus aureus ATCC 6538 (Gram-positive) bacteria. It was found that the MDMCMCh showed higher antibacterial activity than TMChC while MPyMeCh exhibited reduced antibacterial activity against both bacteria at the same DQ level. In comparison to each of the chemical structure, it was found that the antibacterial activity was not only dependent on the DQ but it was also dependent on the positively charged location and the molecular weight.     

Synthesis, structure, and heck cyclization of the syn- and anti-atropisomers of N-acyl-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)-2-iodo-4,6-dimethylaniline

The reaction of 2-iodo-2,4-dimethylaniline with 3,4-dibromo-4-methyltetrahydro-2H-pyran, followed by treatment with acetyl bromide or 4-nitrobenzoyl chloride, gave syn- and anti-atropisomers of N-(2-iodo-4,6-dimethylphenyl)-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)acetamide and N-(2-iodo-4,6-dimethylphenyl)-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)-4-nitrobenzamide. Heating of the acetamide derivative with palladium(II) acetate in the presence of copper(II) acetate and N,N,N′,N′-tetramethylethane-1,2-diamine resulted in heterocyclization to N-acetyl-4a,6,8-trimethyl-1,4a,9,9a-tetrahydropyrano[3,4-b]indole.     

In vitro assessment of N-(benzyl)chitosan derivatives against some plant pathogenic bacteria and fungi

Plant pathogenic bacteria and fungi negatively affect a large number of important fruit and vegetables during the growing season and throughout postharvest storage. Therefore, the current study focuses on the preparation of N-(benzyl)chitosan derivatives as antimicrobial agents to control these microorganisms. Chitosan was reacted with a set of aromatic aldehydes by reductive amination involving formation of the corresponding imines, followed by reduction with sodium borohydride to produce the N-(benzyl)chitosan derivatives. The end products were analyzed using ¹H NMR spectroscopy and the degrees of substitution ranged from 0.12 to 0.29. The antibacterial activity was evaluated in vitro against the crown gall disease Agrobacterium tumefaciens (Family: Rhizobiaceae; Class: Alpha Proteobacteria) and the soft mold disease Erwinia carotovora (Family: Enterobacteriaceae; Class: Gamma Proteobacteria) by the nutrient agar dilution method. A higher activity of chitosan and its derivatives was obtained with N-(o-ethylbenzyl)chitosan with a MIC of 500 mg/L against E. carotovora, while N-(o,p-diethoxybenzyl)chitosan was the most active one against A. tumefaciens with a MIC of 1050 mg/L. In addition, the in vitro antifungal assessment against root rot disease Fusarium oxysporum (Family: Tuberculariaceae; Class: Deuteromycetes) and the leaf spots and blights disease Pythium debaryanum (Family: Pythiaceae; Class: Oomycetes) was tested by a mycelial radial growth technique. The data showed that N-(o,p-diethoxybenzyl)chitosan was the most active one with an EC₅₀ of 400 and 468 mg/L for F. oxysporum and P. debaryanum, respectively. In addition, chitosan derivatives had a detrimental effect on spore germination for F. oxysporum. Most of these derivatives exhibited high inhibition percentage (>90%) of spore germination at 1000 mg/L.     

Biological activity of chitosan–sugar hybrids: specific interaction with lectin

The specific interactions between lectins and chitosan–sugar hybrids, the synthesized chitosan derivatives linking carbohydrate residue to the amino group of chitosan, were investigated. The specific bindings of chitosan‐L ‐fucose (Fuc) hybrid with Ulex europaeus agglutinin I (UEA I, a lectin specific to L ‐Fuc), and chitosan‐N‐acetyl‐D ‐glucosamine (D ‐GlcNAc) hybrid with Concanavalin A (Con A, a lectin specific to D ‐glucose, D ‐mannose and D ‐GlcNAc), were confirmed by a surface plasmon resonance technique. The microscopic observation of Pseudomonas aeruginosa, which was preincubated with the fluorescein isothiocyanate‐labeled chitosan‐L ‐Fuc hybrid, showed bacteria aggregation. The aggregation was thought to be resulted from the specific interaction of the L ‐Fuc residue of the hybrid with PA‐II lectin on the surface of P. aeruginosa. The chitosan‐L ‐Fuc hybrid inhibited P. aeruginosa growth more effectively in comparison with the other hybrids or unmodified chitosan. The enhancement of antimicrobial activity of chitosan‐L ‐Fuc hybrid could be attributed to the specific binding between PA‐II lectin of P. aeruginosa and L ‐Fuc residue of the L ‐Fuc hybrid. Copyright © 2000 John Wiley & Sons, Ltd.     

The synthesis of azahomotryptophane derivatives. The transformation of N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester into 4-(imidazo[1,2-a]azinyl-3)-4-oxohomoalanine derivatives

Azatryptophane homologues, 4-(imidazo[1,2-a]pyridinyl-3)- 9a-9f and 4-(imidazo[1,2-a]pyrimidinyl-3)-4-oxohomoalanine derivatives 9g-91 , were prepared from N,N-dimethyl-N′-(pyridinyl-2)- 6a-6f and N,N-dimethyl-N-(pyriniidinyl-2)formamidines 6g-6i , and (S)-N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester ( 2 ) and its (R,S)-isomer.     

Synthesis and characterization of chitosan grafted poly(N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl) ammonium) initiated by ceric (IV) ion

Grafting of N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl) ammonium (DMMSA) onto chitosan using ceric ammonium nitrate as an initiator was studied under nitrogen atmosphere in 2% wt. acetic acid solution. The grafted polymer was confirmed by FT-IR spectroscopy. The extent of grafting could be adjusted by controlling the appropriate reaction conditions. The maximum percentage of grafting about 50% was obtained under optimum condition. A representative grafted copolymer was characterized by thermogravimetric analysis and chitosan was used as reference.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

Methylation of Chitosan with Iodomethane: Effect of Reaction Conditions on Chemoselectivity and Degree of Substitution

N,N,N‐trimethylchitosan (TMC) was prepared by reacting purified chitosan with iodomethane, in the presence of sodium hydroxide, water and sodium iodide, at room temperature. The reaction medium was N‐methyl‐2‐pyrrolidone. Different samples of TMC were obtained by adding to the reaction medium a fixed volume (5.5 mL) of aqueous NaOH solutions at different concentrations (15, 20, 30 and 40 wt.‐%) and carrying out the reactions for 9 or 24 h. The features observed in the ¹H and ¹³C NMR spectra of these chitosan derivatives, in respect of the chemical shift, number and relative intensity of the signals, depended strongly on the excess of NaOH and H₃CI added to the reaction medium, but when the lowest excess was employed, the characteristics of the derivative were not affected by the reaction time to the same extent. The average degree of quaternization of these N‐methylated derivatives of chitosan ranged from 10.5% to 44.8%, according to the reaction conditions. Increasing the excess of NaOH, in reactions carried out for 9 h, resulted in TMC samples with progressively higher content of trimethylated sites however, the reaction yields were correspondingly lower and O‐alkylation was favored in these cases.

¹H NMR spectrum of sample [A_X]^24h dissolved in D₂O (C_p = 10 g/L).     

Influence of the lyophilizing power of the polymer chain on the relationships in formation of polyelectrolyte-surfactant complexes

Viscometry and turbidimetry were applied to examine the relationships in formation of complexes by poly-1,2-dimethyl-5-vinylpyridinium methyl sulfate, poly-N,N,N,N-trimethyl(methacryloyloxyethyl)ammonium methyl sulfate, and poly[N-benzyl-N,N-dimethyl-N-(methacryloyloxyethyl)]ammonium chloride with sodium dodecyl sulfate.     

Helicity of N,N′-diaryl-trans-1,2-diaminocyclohexane derivatives. Implications for molecular helicity manipulations

Derivatives of trans-1,2-diaminocyclohexane (DACH), useful as chiral ligands, scaffolds and building blocks, differ in their conformation. The conformation of N,N′-diaryl-DACH derivatives was studied by the semiempirical and DFT computational methods and by exciton-coupled circular dichroism. It was found that, contrary to M-helical N,N′-diimine, N,N′-diimide and N,N′-diamide derivatives, the aromatic residues in N,N′-diphenyl derivatives are oriented to form a P-helix for the (R,R)-DACH absolute configuration. The helicity of the bis-aryl system is modified in the case of 1-naphthyl or 2-naphthyl derivatives. Further switching of helicity has been demonstrated by either protonation or mono-N-acetylation of N,N′-diaryl DACH derivatives.     

Synthesis and hybridization affinity of oligodeoxyribonucleotides incorporating 4-N-(N-arylcarbamoyl)deoxycytidine derivatives

Modified oligodeoxynucleotides incorporating 4-N-(N-arylcarbamoyl)-dC derivatives 1a-c were synthesized. The ¹H NMR spectra of 1a-c suggest that the carbamoyl group forms an intramolecular hydrogen bond with the cytosine ring nitrogen atom so that formation of a Watson-Crick base pair with the complementary guanine base is inhibited. The hybridization properties of oligodeoxynucleotides containing 1a-c were investigated by use of T_m analysis. The hybridization properties of 4-N-(N-phenylcarbamoyl)-dC (1a) were similar to those of 4-N-(N-alkylcarbamoyl)-dC derivatives reported previously. In sharp contrast to 1a, it turned out that 4-N-(N-napht-1-yl) and (N-quionol-5-yl)-dC (1b,c) have a unique property as a universal base.     

Synthesis of 1H-pyrrolo[3,2-c]quinoline derivatives via palladium-catalyzed heteroannulation of 2-aryl-3-iodo-4-(phenylamino)quinolines and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines

Palladium(0)/copper iodide catalyzed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinolines with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single-step operation. Conversely, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo PdCl₂(PPh₃)₂/CuI catalyzed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines.     

Dissociation energy of N-H bonds in diatomic aromatic amines

The dissociation energies of N-H bonds (D, kJ/mol) were calculated by the intersecting parabolas method using the kinetic data for the following aromatic diamines: para-phenylenediamine (359.8), N,N′-dimethyl-para-phenylenediamine (348.9), N-dimethyl-N′-methyl-para-phenylenediamine (342.4), N,N′-diphenyl-para-phenylenediamine (352.8), N,N′-diphenylethylenediamine (372.7), N,N′-diheptylethylenediamine (373.3), N,N′-di-(4,4′-ethoxyphenyl)ethylenediamine (363.3), N,N′-di-(4,4′-diisopropylphenyl)-para-phenylenediamine (344.6), 4-{[dimethyl(4-phenylamino)phenoxy)silyl]oxy}-N-phenylaniline (353.4), N,N′-di-β-naphthyl-para-phenylenediamine (354.6), N,N′-di-β-naphthoxy-para-phenylenediamine (353.7), 1,1′-dinaphthyl-2,2′-bis-N,N′-phenyldiamine (372.9), 1,1′-dinaphthyl-2,2′-bis-N,N′-β-naphthyldiamine (384.2), and 2,6-bis[(1E)-1-(2-phenylhydrazin-1-ylidene)ethyl]pyridine (367.9). Individual dissociation energies for the two N-H bonds were determined in N-phenyl-N′-isopropyl-para-phenylenediamine: D(PhN-H) = 352.5 and D(Me₂CHN-H) = 348.7 kJ/mol.     

N,N-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent for the synthesis of pyrimidone and pyrimidine derivatives via Biginelli reaction

A simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2-(1H)one and benzo[4,5]imidazo/thioazo[1,2-a]pyrimidine derivatives has been described using N,N′-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent. This method is found to be efficient and convenient for the synthesis of pyrimidone and pyrimidine derivatives.     

Efficient asymmetric hydrogenation of the C–C double bond of 2-methyl- and 2,3-dimethyl-N-phenylalkylmaleimides by Aspergillus fumigatus

Eight N-phenylalkylmaleimides (four 2-methyl-N-phenylalkylmaleimides and four 2,3-dimethyl-N-phenylalkylmaleimides with an alkyl chain (CH₂)_n (n = 1–4) between the imide N and the benzene ring) were subjected to biotransformation using the fungal strain Aspergillus fumigatus ATCC 26934. All compounds were reduced enantioselectively to their respective succinimides: (R)-2-methyl-N-phenylalkylsuccinimides and (2R,3R)-2,3-dimethyl-N-phenylalkylsuccinimides, with satisfactory conversion rates and high stereoisomeric excesses. NMR analysis using the chiral shift reagent Eu(hfc)₃ showed that enantiomeric excesses were >99%.     

Pd2dba3/P(i-BuNCH2CH2)3N: a highly efficient catalyst for the one-pot synthesis of trans-4-N,N-diarylaminostilbenes and N,N-diarylaminostyrenes

A Pd₂dba₃/P(i-BuNCH₂CH₂)₃N catalyzed one-pot synthesis of unsymmetrically substituted trans-4-N,N-diarylaminostilbenes and both symmetrically and unsymmetrically substituted N,N-diarylaminostyrene derivatives is reported. The procedure involves two or more palladium catalyzed sequential coupling reactions (an amination and an inter-molecular Heck reaction) in one-pot using the same catalyst system with two different aryl halides, including aryl chlorides and hetero aryl halides as the coupling partners.     

Tribromogermyl monochelates — derivatives of N,N-disubstituted 2-hydroxycarboxylic amides

Reactions of GeBr₄ with N,N-dimethyl-2-trimethylsiloxypropionamide (2a), (S)-2-trime-thylsiloxypropionpyrrolidide ((S)-2b), and N,N-dimethyl-O-(trimethylsilyl)mandelamide (2c) afforded pentacoordinated neutral (O,O)-monochelates, viz., N,N-dimethyl-2-tribromoger-myloxypropionamide (3a), (S)-2-tribromogermyloxypropionpyrrolidide ((S)-3b), and N,N-dimethyl-O-(tribromogermyl)mandelamide (3c), respectively. X-ray diffraction study was performed for tribromides 3a, (S)-3b, and 3c, as well as for the N,N-dimethylmandelamide (1c) described earlier. According to the X-ray diffraction data, the Ge atom in tribromides 3a, (S)-3b, and 3c is pentacoordinated and has trigonal bipyramidal configuration with two halogen atoms and oxygen atom of the ether group in the equatorial positions and the halogen atom and the amide oxygen atom in the axial fragment, the bonds in which are somewhat longer as compared to the analogous bonds in tetracoordinated Ge compounds.     

Novel stereoselective syntheses of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N1,N5-dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine

We report two different synthetic approaches for the stereoselective synthesis of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N¹,N⁵-dimethyl-N¹,N⁵-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine 1, an important impurity-reference standard for the chemical characterization of terbinafine. The diamine 1 was obtained in only six steps with a good overall yield starting from commercially available glutaconic acid.     

Reactions of 1,4-bis(tetrazole)benzenes: formation of long chain alkyl halides

The reactions of 1,4-bis[2-(tributylstannyl)tetrazol-5-yl]benzene with α,ω-dibromoalkanes were carried out in order to synthesise pendant alkyl halide derivatives of the parent bis-tetrazole. This led to the formation of several alkyl halide derivatives, substituted variously at N1 or N2 on the tetrazole ring. The crystal structures of 1,4-bis[(2-(4-bromobutyl)tetrazol-5-yl)]benzene (2-N,2-N′), 1,4-bis[(2-(4-bromobutyl)tetrazol-5-yl)]benzene (1-N,2-N′) and 1,4-bis[(2-(8-bromooctyl)tetrazol-5-yl)]benzene (2-N,2-N′) are reported. Further discussion involves the structure of 1,4-bis[2-(6-bromohexyl)-2H-tetrazol-5-yl]benzene (2-N,2-N′) previously reported.     

The Betti base: absolute configuration and routes to a family of related chiral nonracemic bases

A detailed protocol for the resolution of the Betti base [i.e. 1-(α-aminobenzyl)-2-naphthol] was investigated and the absolute configuration of the two isomers was established by means of an X-ray diffractometric study. A series of optically active derivatives was also prepared. The list includes the N-benzyl- and the N,N,O-trimethyl derivatives. The N,N-dimethyl derivative was prepared in racemic form by means of the Betti reaction and was resolved into the two enantiomers with an extremely easy and efficient procedure. The O-methyl derivative was prepared in a racemic form and subjected to resolution. The configuration of each base was determined by correlation with the configuration of the Betti amine.