Novel (±)-trans-ß-lactam ureas: Synthesis, in silico and in vitro biological profiling.

A diastereomeric mixture of racemic 3-phthalimido-b-lactam 2a/2b was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide and imine 1. The amino group at the C3 position of the b-lactam ring was used for further structural upgrade. trans-b-lactam ureas 4a-t were prepared by the condensation reaction of the amino group of b-lactam ring with various aromatic and aliphatic isocyanates. Antimicrobial activity of compounds 4a-t was evaluated in vitro and neither antibacterial nor antifungal activity were observed. Several of the newly synthesized trans-b-lactam ureas 4a-c, 4f, 4h, 4n, 4o, 4p, and 4s were evaluated for in vitro antiproliferative activity against liver hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780), breast adenocarcinoma (MCF7) and untransformed human fibroblasts (HFF1). The b-lactam urea 4o showed the most potent antiproliferative activity against the ovarian carcinoma (A2780) cell line. Compounds 4o and 4p exhibited strong cytotoxic effects against human non-tumor cell line HFF1. The b-lactam ureas 4a-t were estimated to be soluble and membrane permeable, moderately lipophilic molecules (logP 4.6) with a predisposition to be CYP3A4 and P-glycoprotein substrates. The tools PASS and SwissTargetPrediction could not predict biological targets for compounds 4a-t with high probability, pointing to the novelty of their structure. Considering low toxicity risk, molecules 4a and 4f can be selected as the most promising candidates for further structure modifications.

Photochemistry of phthalimidoadamantane dipeptides: effect of amino acid side chain on photocyclization.

A series of dipeptides 1 was synthesized that at the N-site contained 3-(N-phthalimidoadamantane-1-carboxylic acid and at the C-site different aliphatic or aromatic L- or D-amino acids. The photochemical reaction of dipeptides 1 under acetone-sensitized conditions gave simple decarboxylation products 6, and decarboxylation-induced cyclization products 7, as well as some secondary products 8 and 9 formed by elimination of H2O or ring enlargement, respectively. Molecules 9 undergo secondary photoinduced H-abstractions by the phthalimide chromophore, delivering more complex polycycles 11. The photodecarboxylation-induced cyclization to 7 was observed only with phenylalanine (Phe), proline (Pro), leucine (Leu) and isoleucine (Ile). Contrary to dipeptides with Phe, the cyclization takes place with almost complete racemization at the amino acid chiral center, but diastereoselectively giving only one pair of enantiomers. The conducted investigation is important as it provides the breath and the scope of dipeptide cyclizations activated by phthalimides.

Search for new antimicrobials: spectroscopic, spectrometric, and in vitro antimicrobial activity investigation of Ga(III) and Fe(III) complexes with aroylhydrazones.

The in vitro antimicrobial activity of Fe(III) and Ga(III) complexes with N'-(2,3-dihydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (H2L1), N'-(2,4-dihydroxy-phenyl-methylidene)-3-pyridinecarbohydrazide (H2L2), N'-(2,5-dihydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (H2L3), N'-(2-hydroxy-3-methoxyphenyl-methylidene)-3-pyridine-carbohydrazide (H2L4), N'-(2-hydroxy-4-methoxyphenylmethyl-idene)-3-pyridine-carbohydrazide (H2L5), and N'-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbo-hydrazide (H2L6) toward several Gram-positive strains of Staphylococcus aureus, a Gram-negative strain of Escherichia coli, and a yeast Candida albicans were investigated. Fe(III)-complexes do not possess antimicrobial activity against all tested strains at concentrations up to 10 mg mL-1. Ga(III) complexes with dihydroxy derivatives showed selective activity, while the broadest range of antibacterial and antifungal activities was observed for complex with 2-hydroxy-3-methoxy-derivative, ligand H2L5. In addition, the coordination properties of ligands H2L1-H2L3 in solution were investigated by UV-Vis spectroscopy. The stability constants (logK) for Ga(III)-H2L 1:1 complexes in MeOH/H2O 1/1 at pH 2.52 were determined, and amounted to 5.8, 5.68, and 4.7, respectively. Detailed characterization of complexes was performed by high-resolution mass spectrometry. The fragmentation pathways for dimer [Fe2(L1)2]2+, [Fe(HL)2]+, [Ga(HL2)2]+ and adduct ions are given. The comparison with analogue Ga(III) and Fe(III) complexes with compounds H2L4-H2L6 was made as well.

Diverse coordination of aroylhydrazones toward iron(III) in solid state and in solution: spectrometric, spectroscopic and computational study.

The coordination properties of N'-(2-hydroxy-3-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (H2L1), N'-(2-hydroxy-4-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (H2L2) and N'-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (H2L3) toward Fe(III) ions were studied by computational, spectrometric (MS) and spectroscopic methods (UV-Vis, IR and Raman spectroscopy) in solid state and in solution. Free ligands were present in keto-amine form with intramolecular H-bond. In MeOH:H2O 1:1 system, the 1:1 complexes with Fe(III) were formed, characterized by lgK ≥ 6. The coordination to the metal ion was achieved via oxygen and azomethine nitrogen since the hydrolysis of hydrazone bond was suppressed. Unlike the 1:1 stoichiometry in methanolic solution, the composition of the complexes extracted to chloroform was Fe(L)(HL). The release of three protons upon complexation was determined by independent spectrophotometric measurements. The complexes isolated from MeOH/EtOH solution have also stoichiometry 1:2. However, depending on the position of the methoxy substituent, two types of complexes were formed. In Fe(H2L1)2Cl3 and Fe(H2L3)2Cl3, hydrazones acted as neutral ligands, while in Fe(HL2)2Cl the keto-enol tautomeric interconversion and release of one proton per ligand took place. All complexes were analyzed in gas phase as well, using triple quadrupole, ion trap and H/D exchange for determination of labile hydrogens. Based on the fragmentation pathways, the structural isomers were distinguished.

Antimicrobial assesment of aroylhydrazone derivatives in vitro.

Aroylhydrazones 1-13 were screened for antimicrobial and antibiofilm activities in vitro. N'-(2-hydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (2), N'-(5-chloro-2-hydroxyphenyl-methylidene)-3-pyridinecarbohydrazide (10), N'-(3,5-chloro-2-hydroxyphenylmethylidene)-3-pyridinecarbohydrazide (11), and N'-(2-hydroxy-5-nitrophenylmethylidene)-3-pyridinecarbohydrazide (12) showed antibacterial activity against Escherichia coli, with MIC values (in µmol mL-1) of 0.18-0.23, 0.11-0.20, 0.16-0.17 and 0.35-0.37, resp. Compounds 11 and 12, as well as N'-(2-hydroxy-3-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (6) and N'-(2-hydroxy-5- methoxyphenylmethylidene)-3-pyridinecarbohydrazide (8) showed antibacterial activity against Staphylococcus aureus, with the lowest MIC values of 0.005-0.2, 0.05-0.12, 0.06-0.48 and 0.17-0.99 µmol mL-1. N'-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (7) showed antifungal activity against both fluconazole resistant and susceptible C. albicans strains with IC90 range of 0.18-0.1 µmol mL-1. Only compound 11 showed activity against C. albicans ATCC 10231 comparable to the activity of nystatin (the lowest MIC 4.0 ×10-2 vs. 1.7 × 10-2 µmol mL-1). Good activity regarding multi-resistant clinical strains was observed for compound 12 against MRSA strain (MIC 0.02 µmol mL-1) and compounds 2, 6 and 12 against ESBL+ E. coli MFBF 12794, with the lowest MIC for compound 12 (IC50 0.16 µmol mL-1). Anti-biofilm activity was found for compounds 2 (MBFIC 0.015-0.02 µmol mL-1 against MRSA) and 12 (MBFIC 0.013 µmol mL-1 against EBSL+ E. coli). In the case of compound 2 against MRSA biofilm formation, MBFIC values were comparable to those of gentamicin sulphate, whereas in the case of compound 12 and EBSL+ E. coli even more favourable activity compared to gentamicin was observed.

Fine-tuning the effect of π-π interactions on the stability of the NTB phase.

The synthesis and liquid-crystalline properties are reported for novel bent-shaped dimers in which a naphthyl group has been incorporated into the mesogenic cores. In addition to the nematic and twist-bend nematic phase, a new liquid-crystalline phase was observed. The combined experimental and computational study demonstrated how the interplay between the molecular geometry and π-π interactions affects the thermal stability of the twist-bend nematic and nematic phases. Correlation between mesomorphic properties and molecular geometry revealed that a greater conformational diversity leads to a broader distribution of bend-angles and destabilization of the NTB phase. Qualitative correlation between the thermal behaviour and electronic structure of the molecules of a similar geometry suggested that the transition temperatures of both nematic phases depend on the relative contribution of dispersion and electrostatic energies which determines the strength of the π-π interactions. These results provide an insight into how subtle changes in chemical structure can be exploited to tune the intermolecular interactions and influence the thermal stability of the liquid crystalline phase.

Catabolism of terbuthylazine by mixed bacterial culture originating from s-triazine-contaminated soil.

The s-triazine herbicide terbuthylazine (TERB) has been used as the main substitute of atrazine in many EU countries for more than 10 years. However, the ecological consequences of this substitution are still not fully understood. Since the fate of triazine herbicides is primarily dependent on microbial degradation, in this paper, we investigated the ability of a mixed bacterial culture, M3-T, originating from s-triazine-contaminated soil, to degrade TERB in liquid culture and soil microcosms. The M3-T culture grown in mineral medium with TERB as the N source and citrate as the C source degraded 50 mg L(-1) of TERB within 3 days of incubation. The culture was capable of degrading TERB as the sole C and N source, though at slower degradation kinetics. A thorough LC-MS analysis of the biodegradation media showed the formation of hydroxyterbuthylazine (TERB-OH) and N-t-butylammelide (TBA) as major metabolites, and desethylterbuthylazine (DET), hydroxydesethylterbuthylazine (DET-OH) and cyanuric acid (CA) as minor metabolites in the TERB degradation pathway. TBA was identified as a bottleneck in the catabolic pathway leading to its transient accumulation in culture media. The supplementation of glucose as the exogenous C source had no effect on TBA degradation, whereas citrate inhibited its disappearance. The addition of M3-T to sterile soil artificially contaminated with TERB at 3 mg kg(-1) of soil resulted in an accelerated TERB degradation with t 1/2 value being about 40 times shorter than that achieved by the native microbial community. Catabolic versatility of M3-T culture makes it a promising seed culture for accelerating biotransformation processes in s-triazine-contaminated environment.

Structural investigations of aroylhydrazones derived from nicotinic acid hydrazide in solid state and in solution.

Structural forms of aroylhydrazones derived from nicotinic acid hydrazide have been studied in the solid state by FT-IR spectroscopy and in solution by NMR, UV-Vis and ATR spectroscopy. The studied compounds were N'-benzylidene-3-pyridinecarbohydrazide (1), N'-(2,4-dihydroxyphenylmethylidene)-3-pyridinecarbohydrazide (2), N'-(5-chloro-2-hydroxyphenylmethylidene)-3-pyridinecarbohydrazide (3), and N'-(3,5-dichloro-2-hydroxymethoxyphenylmethylidene)-3-pyridinecarbohydrazide (4). The compound 1 adopted the most stable ketoamine form (form I, -CO-NH-N=C-) in the solid state as well as in various organic solvents. In mixtures of organic solvents with water the UV-Vis and ATR spectra implied intermolecular hydrogen bonding of 1 with water molecules. The presence of both tautomeric forms I and II (form II, -COH=N-N=C-) was proposed for the solid substance and highly concentrated solutions of 2, whereas form I was detected as the predominant one in diluted solutions. For compounds 3 and 4 a coexistence of forms I and III (form III, -CO-NH-NH-C=C-CO-) was noticed in the solid state and in polar protic organic solvents. The conversion to form III was induced by increasing the water content in the solvent mixtures. This process was the most pronounced for compound 4. When exposed to daylight, an appearance of a new band was observed during time in the UV-Vis spectrum of 4 in organic solvent/water 1/1 mixtures, which implied that tautomeric interconversion was most likely followed by E/Z isomerisation.

Molecular recognition of indole derivatives by polymers imprinted with indole-3-acetic acid: a QSPR study.

Three molecularly imprinted polymers (MIPs) were prepared using the phytohormone indole-3-acetic acid (IAA) as a template molecule, 4-vinylpyridine (MIP-1 and MIP-2) or N,N-dimethylaminoethyl methacrylate (MIP-3) as functional monomers, ethylenglycol dimethacrylate as a cross linker and acetonitrile (MIP-1), a methanol-water mixture (MIP-2) or chloroform (MIP-3) as porogens. Retention factors for IAA and 29 indole derivatives were determined by high-performance liquid chromatography, using the molecularly imprinted polymers as stationary phases and acetonitrile as an eluent. High correlations between selectivity factors of above mentioned polymers indicate that their retention mechanisms are basically the same. A quantitative structure-property relationships analysis revealed that the presence of the terminal carboxyl group on the 3-side chain plays an essential role in the binding of the indole derivatives to the polymers. The derivatives without the carboxyl group exhibit a drastically lower affinity toward the polymers. Another factor which favors the binding is electronic density of indole nucleus. Substituents with electro-withdrawing properties enhance the binding, while electro-donating substituents have the opposite effect. The length of the 3-side chain also affects the binding. Indole-3-carboxylic acid having the carboxyl group directly attached to the ring as well as the derivatives whose side chain is longer than that of IAA bind to the polymers with a lower affinity.

Structural investigation of aroylhydrazones in dimethylsulphoxide/water mixtures.

Molecular structures of aroylhydrazones derived from salicylaldehyde, o-vanilin and nicotinic acid hydrazide in DMSO and DMSO/H(2)O mixtures have been studied by NMR, UV-Vis, ATR and Raman spectroscopy. The addition of water to the system did not induce the tautomeric conversion of the existing form constituted of the ketoamino hydrazide part and the enolimino aldehyde part, but it was involved in the formation of hydrated molecules. Vibrational spectra (ATR and Raman) clearly indicated hydrogen bonding of the studied hydrazones through the carbonyl, amino and hydroxyl groups with water molecules. Increasing the water content conversion from E to Z isomer was not observed.

Performance of brush-type HPLC chiral stationary phases with tertiary amide in the connecting tether.

The replacement of the N-H hydrogen of the secondary amide-tethered Pirkle-concept N-(3,5-dinitrobenzoyl)-L-leucine derived chiral stationary phase with various pi-basic or aliphatic groups improved the chiral discrimination ability of new chiral stationary phases, based on the leucine- or alanine-derived chiral selector, for the enantiomers of various racemic neutral analytes with amide functional groups. Retention times decreased while separation and resolution factors increased, thus proving the role of pi-donor aromatic unit as an electron-rich shield in the front of a silica surface. In general, chiral stationary phase (CSP) 5 with the 3,5-dimethylphenyl unit showed best performance, while CSP 3, with phenyl unit, and CSP 7, with 1-naphthyl unit in the tertiary amide connecting tether, were less efficient.

Enantioseparation of racemic 4-aryl-3,4-dihydro-2(1H)-pyrimidones on chiral stationary phases based on 3,5-dimethylanilides of N-(4-alkylamino-3,5-dinitro)benzoyl L-alpha-amino acids.

Three novel chiral packing materials for high-performance liquid chromatography were prepared by covalently binding of (2S)-N-(3,5-dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]propan-amide (7), (2S)-N-(3,5-dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]-4-methylpentanamide (8), and (2S)-N-(3,5-dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonyl-amino]-2-phenylacetamide (9) to aminopropyl silica. The resulting chiral stationary phases (CSPs 1-3) proved effective for the resolution of racemic 4-aryl-3,4-dihydro-2(1H)-pyrimidone derivatives (TR 1-14). The mechanism of their enantioselection, supported by the elution order of (S)-TR 13 and (R)-TR 13 and molecular modeling of the complex of the slower running (S)-TR 13 with CSP 1 is discussed.

Enantiomerization of 3-carbethoxy-l,4-benzodiazepin-2-one: combined chiral HPLC and spectroscopic study.

Recently developed chiral HPLC columns CHIRIS AD1 and CHIRIS AD2 have been demonstrated to separate racemic, configurationally unstable ethyl-7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-carboxylate (1) and its 3-methyl congener 2; fast on-column enantiomerization of configurationally unstable 1 was observed, however. Addition of 0.1% of AcOH to the eluting mixture inhibits enantiomerization, whereas the same percentage of Et(3)N completely precludes enantioseparation, suggesting base-catalysis by free beta-aminoethyl groups, present in low percentage in chiral stationary phase (CSP). When both CSPs were prepared under conditions of nonexhaustive acylation by N-DNB-alpha-aminoacids, no separation of 1 was observed. The rate of enantiomerization on CHIRIS AD2 was determined at 25 degrees C, the mechanism is discussed, and experimental results correlated with calculated relative stabilities of the tautomers la-c. Absolute (3S) configuration of (+) enantiomers of 1 and 2 was determined by comparison of their eluation profile to that of (+/-)-3 and (3S)-(+)-3, taking into account relative (psia or psie) configuration of the prevailing conformer in solution.