Antioxidant Activity of 3-[N-(Acylhydrazono)ethyl]-4-hydroxy-coumarins.

A series of 3-acylhydrazono-4-hydroxycoumarins were synthesized via condensation of 3-acetyl-4-hydroxycoumarin with appropriate hydrazides. The structures of the newly-synthesized compounds were characterized by spectral and elememental analysis or HRMS measurements. Their antioxidant properties were evaluated by using scavenging effects on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical as well as inhibition of lipid peroxidation. Moreover, their ability to inhibit in vitro soybean lipoxygenase has been investigated. They were found to be capable of rapid inactivation of alkylperoxy radicals.

One-pot five-component synthesis of spirocyclopenta[b]chromene derivatives and their acid-catalyzed rearrangement.

The reaction of the zwitterionic intermediate, generated in situ from either tert-butylisocyanide or cyclohexylisocyanide and acetylenedicarboxylates, with 3-cyanochromones is described, whereupon spirochromenofuran derivatives 5 or 6 were obtained in good yields. The subsequent acid-catalyzed rearrangement of the isolated 2-imino-spirochromenofurans 5 to 2-amino-spirochromenofurans 7 has also been studied. Rational mechanistic schemes for the formation of compounds 5, 6, and 7 are proposed. The structure elucidation of the products was accomplished by 1D and 2D NMR experiments and confirmed by X-ray crystallographic analysis. Full assignment of all (1)H and (13)C NMR chemical shifts has been unambiguously achieved with the aid of DFT/GIAO calculations.

One-pot synthesis of functionalized spirobenzofuranones via MCR involving 3-cyanochromones.

Another aspect concerning chromone chemistry leading to the one-pot synthesis of functionalized novel spirobenzofuranones has been described. The synthesis involves reaction of the zwitterionic intermediates formed by the 1:1 interaction between isocyanides and acetylenecarboxylates with 3-cyanochromones, whereupon through an unexpected and unprecedented reaction of the chromone moiety the isolated benzofuranones are formed. The regioselectivity of the reaction was investigated by DFT calculations. The geometries of the intermediates, transition structures, and intermediate products, leading to the final products, were optimized using the B3LYP functional with the 6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments. Full assignment of all (1)H and (13)C NMR chemical shifts has been achieved. A plausible mechanistic rationale is proposed.

Synthesis of 2-keto-imidazoles utilizing N-arylamino-substituted N-heterocyclic carbenes.

A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-, and 2-cinnamoyl-substituted imidazoles in very good yields has been developed. The reaction employs novel nitrogen heterocyclic carbenes (NHCs), namely, N-arylamino-substituted NHCs, formed in situ from the corresponding imidazolium salts, and subsequent reaction with aromatic, heteroaromatic, and cinnamic aldehydes without utilizing transition metals or expensive specialized catalysts.

One-pot synthesis of chromenylfurandicarboxylates and cyclopenta[b]chromenedicarboxylates involving zwitterionic intermediates. A DFT investigation on the regioselectivity of the reaction.

The reaction of 1:1 zwitterionic intermediates generated in situ from either tert-butylisocyanide or cyclohexylisocyanide and acetylenedicarboxylates with 3-formylchromones is described, whereupon either chromenylfurandicarboxylates or cyclopenta[b]chromenedicarboxylates are formed, depending on the nature of the chromone 6-position substituent and also on the acetylene ester group. In addition, from the reaction with a 1:2 zwitterionic intermediate, cyclohepta[b]chromenetetracarboxylates are isolated. The regioselectivity of the reaction was also investigated by DFT calculations. The geometries of the reactants, intermediate zwitterions, transition structures, and intermediate products, leading to the final products, were optimized using the B3LYP functional with the 6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments. Full assignment of all (1)H and (13)C NMR chemical shifts has been achieved. Plausible mechanistic schemes are provided.

Towards Elucidating Carnosic Acid Biosynthesis in Lamiaceae: Functional Characterization of the Three First Steps of the Pathway in Salvia fruticosa and Rosmarinus officinalis.

Carnosic acid (CA) is a phenolic diterpene with anti-tumour, anti-diabetic, antibacterial and neuroprotective properties that is produced by a number of species from several genera of the Lamiaceae family, including Salvia fruticosa (Cretan sage) and Rosmarinus officinalis (Rosemary). To elucidate CA biosynthesis, glandular trichome transcriptome data of S. fruticosa were mined for terpene synthase genes. Two putative diterpene synthase genes, namely SfCPS and SfKSL, showing similarities to copalyl diphosphate synthase and kaurene synthase-like genes, respectively, were isolated and functionally characterized. Recombinant expression in Escherichia coli followed by in vitro enzyme activity assays confirmed that SfCPS is a copalyl diphosphate synthase. Coupling of SfCPS with SfKSL, both in vitro and in yeast, resulted in the synthesis miltiradiene, as confirmed by 1D and 2D NMR analyses (1H, 13C, DEPT, COSY H-H, HMQC and HMBC). Coupled transient in vivo assays of SfCPS and SfKSL in Nicotiana benthamiana further confirmed production of miltiradiene in planta. To elucidate the subsequent biosynthetic step, RNA-Seq data of S. fruticosa and R. officinalis were searched for cytochrome P450 (CYP) encoding genes potentially involved in the synthesis of the first phenolic compound in the CA pathway, ferruginol. Three candidate genes were selected, SfFS, RoFS1 and RoFS2. Using yeast and N. benthamiana expression systems, all three where confirmed to be coding for ferruginol synthases, thus revealing the enzymatic activities responsible for the first three steps leading to CA in two Lamiaceae genera.

One-pot microwave assisted synthesis of new 2-alkoxycarbonylmethylene-4-oxo-1,5-benzo-, naphtho-, and pyridodiazepines and assessment of their cytogenetic activity.

1,5-Benzo-, naphtho-, and pyridodiazepines 3 have been synthesized in excellent yields in one-step from the reaction of o-phenylenediamines with acetonedicarboxylates through microwave assisted acid catalysis. In order to ascertain their cytogenetic activity in vitro at doses equivalent to the per os doses of common 1,4-benzodiazepine drugs, Sister Chromatid Exchanges (SCEs) were employed, and for the determination of cytostaticity the Proliferation Rate Index (PRI) on lymphocytes of human whole blood cultures was estimated. It was found that benzodiazepines 3a, 3c, and 3e exhibit significant cytoprotection, but mild cytostatic effect (a statistically significant reduction of SCEs and a confined decrease of PRI values at similar concentrations). The most active compound was found to be 3e.

One-pot microwave assisted synthesis under green chemistry conditions, antioxidant screening, and cytotoxicity assessments of benzimidazole Schiff bases and pyrimido[1,2-a]benzimidazol-3(4H)-ones.

The synthesis of a number of benzimidazole Schiff bases 3 and 3-oxo-pyrimido[1,2-a]benzimidazoles 4 in excellent yields by a one-step sequence from the reaction of 2-aminobenzimidazole under green chemistry conditions is described. Structural assignments of the new compounds as well as complete assignment of (1)H and (13)C NMR signals have been unambiguously achieved based on the analysis of their (1)H and (13)C NMR (1D and 2D), IR, MS and elemental analysis data. To the synthesized Schiff bases the E-configuration was assigned on the basis of comparison of experimental and calculated (DFT) (13)C NMR chemical shifts. Compounds 3 and 4 were evaluated as inhibitors of lipoxygenase (LOX) and of lipid peroxidation (LPO). All the tested derivatives showed inhibition of lipid peroxidation, whereas most of them were found to have higher activation than the reference compound trolox; The Schiff bases 3e, 3h, and 3i, and the pyrimidobenzimidazoles 4a, 4e and 4f were found to be the most potent. The most potent LOX inhibitor within the subset of Schiff bases was found compound 3i, followed by 3f, whereas compounds 4a and 4g were found the most potent of the 3-oxo-pyrimido[1,2-a]benzimidazole group. Moreover, some cytotoxicity assessments were undertaken, whereupon it was found that Schiff base 3i and pyrimidobenzimidazoles 4e and 4f did not exhibit cytotoxicity at similar concentrations resembling thus the inhibitory activity of lipid peroxidation. The most cytotoxic Schiff base and pyrimidobenzimidazole were found to be 3d and 4c, respectively.

Cytogenetic activity of newly synthesized 1,5-benzodiazepines in normal human lymphocyte cultures.

INTRODUCTION: Many different types of benzodiazepine medications exist to treat a wide array of psychological and physical diseases based on dosage and implications. Benzodiazepines are generally considered as safe and effective drugs in short term; however, cognitive impairments and paradoxical effects occasionally occur. Our recent studies have shown that some 1,4-benzodiazepines exhibit cytogenetic activity (alprazolam, diazepam, and lorazepam) in normal human lymphocyte cultures. 1,5-Benzodiazepine derivatives are used in the synthesis of fused ring compounds, to study the chemical structure-pharmacological activity correlation. We synthesized four compounds of this category with small structural differences. AIM: The aim of this study was to investigate their cytogenetic activity in vitro at doses equivalent to the per os doses of the used 1,4-benzodiazepines. Sister chromatid exchanges (SCEs), proliferation rate index, and mitotic index were evaluated in lymphocytes of peripheral blood cultures from two healthy donors. RESULTS: Three of the newly synthesized compounds exhibited positive cytogenetic activity (statistically significant reduction of SCEs, p < 0.01, t-test), without showing cytostatic properties. CONCLUSION: The observed reduction of the lymphocytes' SCEs because of 1,5-benzodiazepines' activity is remarkable and requires further investigation to improve pharmacological effects.

1,5-Benzoxazepines vs 1,5-benzodiazepines. one-pot microwave-assisted synthesis and evaluation for antioxidant activity and lipid peroxidation inhibition.

Amino-1,5-benzoxazepines 2 and 5 and hydroxyl-1,5-benzodiazepines 3 and 6 have been synthesized in one-pot solvent-free conditions from 2,3-diaminophenol and ketones through microwave assisted acid catalysis, the benzoxazepine/benzodiazepine ratio depending on the R(1) and R(3) aryl substituents. The otherwise inaccessible and unknown 2,2-dimethyl-4-aryl-1,5-benzodiazepines 8 were also prepared in an analogous manner. The reaction mechanism was investigated by means of DFT calculations. Structural assignments of the new compounds as well as complete assignment of (1)H and (13)C NMR signals have been unambiguously achieved on the basis of the analysis of their (1)H and (13)C NMR (1D and 2D), IR, MS, and elemental analysis data, whereas the presence of an amino group in 5 and of a hydroxyl in 6 was confirmed by derivatization. Compounds 2, 3, 5f, 6a, 6c, 6d, 6f, 6h, 8c, and 12 were evaluated as antioxidants and lipid peroxidation inhibitors in vitro. Compound 6f was also evaluated as anti-inflammatory agent in vivo. Compounds 2 and 6f were found to be the most potent as inhibitors of lipoxygenase and of lipid peroxidation, respectively.