New 3-(Dibenzyloxyphosphoryl)isoxazolidine Conjugates of N1-Benzylated Quinazoline-2,4-diones as Potential Cytotoxic Agents against Cancer Cell Lines.

In this study, a new series of cis and trans 5-substituted-3-(dibenzyloxyphosphoryl)isoxazolidines 16a-g were synthesized by the 1,3-dipolar cycloaddition reaction of N-benzyl-C-(dibenzyloxyphosphoryl)nitrone and selected N1-allyl-N3-benzylquinazoline-2,4-diones. All the obtained trans-isoxazolidines 16a-g and the samples enriched in respective cis-isomers were evaluated for anticancer activity against three tumor cell lines. All the tested compounds exhibited high activity against the prostate cancer cell line (PC-3). Isoxazolidines trans-16a and trans-16b and diastereoisomeric mixtures of isoxazolidines enriched in cis-isomer using HPLC, namely cis-16a/trans-16a (97:3) and cis-16b/trans-16b (90:10), showed the highest antiproliferative properties towards the PC-3 cell line (IC50 = 9.84 ± 3.69-12.67 ± 3.45 µM). For the most active compounds, induction apoptosis tests and an evaluation of toxicity were conducted. Isoxazolidine trans-16b showed the highest induction of apoptosis. Moreover, the most active compounds turned out safe in vitro as none affected the cell viability in the HEK293, HepG2, and HSF cellular models at all the tested concentrations. The results indicated isoxazolidine trans-16b as a promising new lead structure in the search for effective anticancer drugs.

Synthesis and Antioxidant Activity of N-Benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine Oxides.

The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel N-benzyl-2-[4-(aryl)-1H-1,2,3-triazol-1-yl]ethan-1-imine oxides 10a-d are reported herein. The nitrones 10a-d were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant tests were used for in vitro antioxidant assays, namely, interaction with the stable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as well as with the water-soluble azo compound AAPH (2,2'-azobis(2-amidinopropane) dihydrochloride), competition with DMSO for hydroxyl radicals, and the scavenging of cationic radical ABTS•+ (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical cation). Nitrones 10b, 10c, and 10d, having the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, exhibited high interaction with DPPH (64.5-81% after 20 min; 79-96% after 60 min), whereas nitrone 10a with unfunctionalized phenyl group showed the lowest inhibitory potency (57% after 20 min, 78% after 60 min). Nitrones 10a and 10d, decorated with phenyl and 4-fluoro-3-methylphenyl motif, respectively, appeared the most potent inhibitors of lipid peroxidation. The results obtained from radical cation ABTS•+ were not significant, since all tested compounds 10a-d showed negligible activity (8-46%), much lower than Trolox (91%). Nitrone 10c, bearing the 2,4-difluorophenyl motif, was found to be the most potent LOX inhibitor (IC50 = 10 µM).

Antimicrobial Activity and Toxicity of Newly Synthesized 4-[4-(benzylamino)butoxy]-9H-carbazole Derivatives.

One of the main challenges of medicinal chemistry is the search for new substances with antimicrobial potential that could be used in the fight against pathogenic microorganisms. Therefore, the antimicrobial activity of newly synthesized compounds is still being investigated. Carbazole-containing compounds appear to be promising antibacterial, antifungal, and antiviral agents. The aim of this study was to examine the antimicrobial potential and toxicity of newly synthesized isomeric fluorinated 4-[4-(benzylamino)butoxy]-9H-carbazole derivatives. Their antimicrobial activity against bacteria and fungi was tested according to CLSI guidelines. Similarly to previously studied carbazole-containing compounds, the tested derivatives showed the ability to effectively inhibit the growth of Gram-positive bacteria. The addition of carbazole derivatives 2, 4, and 8 at the concentration of 16 µg/mL caused the inhibition of S. aureus growth by over 60%. The MIC value of compounds 2-5 and 7-10 was 32 µg/mL for Staphylococcus strains. Gram-negative strains of E. coli and P. aeruginosa were found to be more resistant to the tested carbazole derivatives. E. coli cells treated with compounds 3 and 8 at a concentration of 64 µg/mL resulted in a greater-than-40% reduction in bacterial growth. In the case of the P. aeruginosa strain, all compounds in the highest concentration that we tested limited growth by 35-42%. Moreover, an over-60% inhibition of fungal growth was observed in the cultures of C. albicans and A. flavus incubated with 64 µg/mL of compounds 2 or 7 and 1 or 4, respectively. The hemolysis of red blood cells after their incubation with the tested carbazole derivatives was in the range of 2-13%. In the case of human fibroblast cells, the toxicity of the tested compounds was higher. Derivative 1, functionalized with fluorine in position 2 and its hydrobromide, was the least toxic. The obtained results indicated the antimicrobial potential of the tested 4-[4-(benzylamino)butoxy]-9H-carbazole derivatives, especially against S. aureus strains; therefore, it is worth further modifying these structures, in order to enhance their activity against pathogenic microorganisms.

Synthesis of Enantiomerically Enriched Protected 2-Amino-, 2,3-Diamino- and 2-Amino-3-Hydroxypropylphosphonates.

Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, N-protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl (R)- and (S)-2-(N-Boc-amino)propylphosphonates were obtained via direct regiospecific hydrogenolysis of the respective enantiomer of (R)- and (S)-N-Boc-(aziridin-2-yl)methylphosphonates. N-Boc-protected (R)- and (S)-2,3-diaminopropylphosphonates were synthesized from (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates via a regiospecific ring-opening reaction with neat trimethylsilyl azide and subsequent reduction of (R)- and (S)-2-(N-Boc-amino)-3-azidopropylphosphonates using triphenylphosphine. On the other hand, treatment of the corresponding (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates with glacial acetic acid led regiospecifically to the formation of (R)- and (S)-2-(N-Bn-amino)-3-acetoxypropylphosphonates.

Design and synthesis of a new series of hybrids of functionalised N1-[(1H-1,2,3-triazol-4-yl)methyl]quinazoline-2,4-dione with antiviral activity against Respiratory Syncytial Virus.

In this study, a series of 48 hybrids of the functionalised 1-[(1H-1,2,3-triazole-4-yl)methyl]quinazoline-2,4-dione 17-22 were synthesised and evaluated for potential antiviral activity. The new hybrids were designed to contain a diethoxyphosphoryl group connected to the triazole moiety via ethylene or propylene linker, and in which the benzyl or benzoyl function is substituted at N3 in the quinazoline-2,4-dione moiety. The Cu(I)-catalyzed Hüisgen dipolar cycloaddition of azidophosphonates 23 and 24 with the respective N1-propargylquinazoline-2,4-diones 26aa-26ag, 26ba-26bg, 27aa-27ad and 27ba-27bd was applied for the syntheses of the designed compounds. All final hybrids 17-22 and N3-functionalised N1-propargylquinazoline-2,4-diones 26 and 27 were subsequently evaluated for their antiviral activity toward a broad range of DNA and RNA viruses. Importantly, hybrids 19be-19bg and 20be-20bg showed profound antiviral activities against Respiratory Syncytial Virus (RSV) with EC50 values in the lower micromolar range, with activity against viral strains of both subtypes (RSV A and B). In addition, several compounds also exerted some weak antiviral activity against varicella zoster virus. Finally, 19 ag was the only compound that showed antiviral potency against human cytomegalovirus, although with rather weak inhibitory activity. Notably, none of the tested compounds was cytotoxic toward uninfected cell lines used for the antiviral assays at a concentration up to 100 µM, returning interesting therapeutic indices for respiratory syncytial virus.

The Effect of the Stress-Signalling Mediator Triacontanol on Biochemical and Physiological Modifications in Dracocephalum forrestii Culture.

Triacontanol (TRIA) has been reported to influence signal transduction in the crosstalk triggered by various stress factors. As a signal player, it is also known to affect many physiological processes, including enhancing the biosynthesis of secondary metabolites. Such knowledge can be used to direct or boost the production of bioactive secondary compounds without stress induction. Therefore, the aim of this study is to evaluate the use of TRIA as a factor stimulating the growth and production of bioactive compounds in the shoot culture of Dracocephalum forrestii. TRIA was applied at three concentrations (2.5, 5, and 10 µM), alone or in combination with phytohormones (6-benzylaminopurine and indole-3-acetic acid). After five weeks, growth and physiochemical parameters (chlorophyll content, antioxidant enzyme activity, and phenolic acid level) were determined. The results indicate that TRIA application significantly increased shoot dry weight, chlorophyll content, antioxidant enzyme activities (superoxide dismutase, peroxidase, and catalase), and total polyphenol level; it also influenced the multiplication ratio in combination with growth regulators. The greatest antioxidant enzyme activity was observed for 5 µM TRIA in hormone-free medium, while the most significant secondary metabolite production was obtained for phytohormone-containing medium supplemented with 10 µM TRIA: total phenolic acid content (19.4 mg/g dry weight) was twice that of the control. Hence, the TRIA application appears to be a valuable biotechnology technique for modifying plant metabolite production.

Design, Synthesis, Anti-Varicella-Zoster and Antimicrobial Activity of (Isoxazolidin-3-yl)Phosphonate Conjugates of N1-Functionalised Quinazoline-2,4-Diones.

Dipolar cycloaddition of the N-substituted C-(diethoxyphosphonyl)nitrones with N3-allyl-N1-benzylquinazoline-2,4-diones produced mixtures of diastereoisomeric 3-(diethoxyphosphonyl)isoxazolidines with a N1-benzylquinazoline-2,4-dione unit at C5. The obtained compounds were assessed for antiviral and antibacterial activities. Several compounds showed moderate inhibitory activities against VZV with EC50 values in the range of 12.63-58.48 µM. A mixture of isoxazolidines cis-20c/trans-20c (6:94) was found to be the most active against B. cereus PCM 1948, showing an MIC value 0.625 mg/mL, and also was not mutagenic up to this concentration.

Synthesis of Four Enantiomers of (1-Amino-3-Hydroxypropane-1,3-Diyl)Diphosphonic Acid as Diphosphonate Analogues of 4-Hydroxyglutamic Acid.

All the enantiomers of (1-amino-3-hydroxypropane-1,3-diyl)diphosphonic acid, newly design phosphonate analogues of 4-hydroxyglutamic acids, were obtained. The synthetic strategy involved Abramov reactions of diethyl (R)- and (S)-1-(N-Boc-amino)-3-oxopropylphosphonates with diethyl phosphite, separation of diastereoisomeric [1-(N-Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates as O-protected esters, followed by their hydrolysis to the enantiomeric phosphonic acids. The absolute configuration of the enantiomeric phosphonates was established by comparing the 31P NMR chemical shifts of respective (S)-O-methylmandelic acid esters obtained from respective pairs of syn- and anti-[1-(N-Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates according to the Spilling rule.

Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia-Reperfusion.

Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named 9a-i. The neuroprotective properties of nitrones, 9a-i, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, 9a-i, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN) and are similar to N-acetyl-L-cysteine (NAC), a well-known antioxidant and neuroprotective agent. The nitrones with the highest neuroprotective capacity were those containing purine nucleobases (nitrones 9f, g, B = adenine, theophylline), followed by nitrones with pyrimidine nucleobases with H or F substituents at the C5 position (nitrones 9a, c). All of these possess EC50 values in the range of 1-6 µM and maximal activities higher than 100%. However, the introduction of a methyl substituent (nitrone 9b, B = thymine) or hard halogen substituents such as Br and Cl (nitrones 9d, e, B = 5-Br and 5-Cl uracil, respectively) worsens the neuroprotective activity of the nitrone with uracil as the nucleobase (9a). The effects on overall metabolic cell capacity were confirmed by results on the high anti-necrotic (EC50's ≈ 2-4 µM) and antioxidant (EC50's ≈ 0.4-3.5 µM) activities of these compounds on superoxide radical production. In general, all tested nitrones were excellent inhibitors of superoxide radical production in cultured neuroblastoma cells, as well as potent hydroxyl radical scavengers that inhibit in vitro lipid peroxidation, particularly, 9c, f, g, presenting the highest lipoxygenase inhibitory activity among the tested nitrones. Finally, the introduction of two nitrone groups at 9a and 9d (bis-nitronas 9g, i) did not show better neuroprotective effects than their precursor mono-nitrones. These results led us to propose nitrones containing purine (9f, g) and pyrimidine (9a, c) nucleobases as potential therapeutic agents for the treatment of cerebral ischemia and/or neurodegenerative diseases, leading us to further investigate their effects using in vivo models of these pathologies.

Synthesis and Antioxidant Properties of Novel 1,2,3-Triazole-Containing Nitrones.

Herein, we report the synthesis and antioxidant capacity of twelve novel 1,2,3-triazole-containing nitrones such as N-(2-(4-aryl-1H-1,2,3-triazol-1-yl)ethylidene)methanamine oxides 8a-f and N-(2-(4-aryl)-1H-1,2,3-triazol-1-yl)ethylidene)-2-methylpropan-2-amine oxides 9a-f, bearing an N-methyl, and an N-t-butyl substituent, respectively, at the nitrogen of the nitrone motif. Nitrones 8 and 9 were studied with regard to their antioxidant ability, as well as their ability to inhibit soybean lypoxygenase (LOX), and their in vitro antioxidant activity. For this, we used three different antioxidant assays, such as that featuring the interaction with the water-soluble azo compound AAPH for the inhibition of lipid peroxidation (LP), the competition with the DMSO for scavenging hydroxyl radicals, and the ABTS•+-decolorization assay. t-Butyl nitrone 9e, bearing the 2,4-difluorophenyl motif, showed a strong LP inhibitory effect (100%), close to the reference compound Trolox (93%), being the most potent LP inhibitor (LPi) of the whole series of tested nitrones. Nitrones 9d, 9e and 9f, bearing the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, were almost equipotent, and the most potent hydroxyl radical scavengers (~100%), more potent than Trolox (88%), were used as a reference compound. Regarding the LOX inhibition, the most potent inhibitor was the t-butyl substituted nitrone 9f (27 µM), bearing the 4-fluoro-3-methylphenyl motif, being 60-fold less potent than NDGA (0.45 µM), which was used as the standard in this test. The results from the antioxidant determination in the ABTS radical cation (ABTS•+) decolorization assay were not significant. N-Methyl nitrone 8f, bearing the 4-fluoro-3-methylphenyl motif, was the only promising representative, with a value of 34.3%, followed by nitrone 9f (16%). From the antioxidant analyses, we have identified N-(2-(4-(4-fluoro-3-methylphenyl)-1H-1,2,3-triazol-1-yl)ethylidene)-2-methylpropan-2-amine oxide (9f), bearing t-butyl and 4-fluoro-3-methylphenyl motifs in its structure, as the most balanced and potent antioxidant agent among the tested nitrones, as it was the most potent LOX inhibitor (27 µM), an extremely efficient and potent hydroxyl radical scavenger (99.9%), as well as one of the most potent LPi (87%) and ABTS•+ scavengers (16%).

Evaluation of the Antimicrobial Potential and Toxicity of a Newly Synthesised 4-(4-(Benzylamino)butoxy)-9H-carbazole.

One of the greatest threats to human and animal health is posed by infections caused by drug-resistant bacterial strains. Therefore, newly synthesised substances are tested for their antimicrobial activity. Carbazole derivatives seem to be promising antibacterial agents. This study aimed at investigating the toxicity and activity of newly synthesised, functionalised carbazole derivative 2 (4-(4-(benzylamino)butoxy)-9H-carbazole) against various microorganisms. Its antimicrobial potential against Gram-positive and Gram-negative bacteria, yeast, and filamentous fungi was examined according to CLSI (Clinical and Laboratory Standards Institute) standards. The tested compound was found to efficiently inhibit the growth of Gram-positive strains. The addition of carbazole derivative 2 at the concentration of 30 µg/mL caused inhibition of bacterial growth by over 95%. Moreover, about 50 and 45% limitation of Pseudomonas aeruginosa and Aspergillus flavus growth was observed in the samples incubated with the addition of 20 and 60 µg/mL of the compound, respectively. Its addition to the microbial cultures caused an increase in the permeability of the cellular membrane. Slight haemolysis of red blood cells was observed after 24-h treatment with carbazole derivative 2. On the other hand, human fibroblasts were found to be more sensitive to its effects. The activity of the tested compound indicates a possibility of its further modification in order to obtain effective drugs, especially against drug-resistant staphylococci.

Novel N-Substituted 3-Aryl-4-(diethoxyphosphoryl)azetidin-2-ones as Antibiotic Enhancers and Antiviral Agents in Search for a Successful Treatment of Complex Infections.

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3-H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5-97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at ß-lactamase, thus protecting the antibiotic from undesirable biotransformation.

Synthesis of Functionalized Diethyl(pyrrolidin-2-yl)phosphonate and Diethyl(5-oxopyrrolidin-2-yl)phosphonate.

Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of O,O-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into O,O-diethyl 3-aminomethyl-4-hydroxy(pyrrolidin-2-yl)phosphonate was accomplished by mesylation followed by hydrogenolysis to undergo intramolecular cyclization and the introduction of amino group via ammonolysis. Stereochemistry of the isoxazolidine cycloadducts, as well as the final functionalized (pyrrolidin-2-yl)- and (5-oxopyrrolidin-2-yl)phosphonates were established based on conformational analyses using vicinal H-H, H-P, and C-P couplings and supported by the observed diagnostic NOESY correlation signals.

Synthesis of Enantiomerically Pure N-Boc-Protected 1,2,3-Triaminopropylphosphonates and 1,2-Diamino-3-Hydroxypropylphosphonates.

All possible isomers of 1,2,3-tri(N-tert-butoxycarbonylamino)propylphosphonate 6 were synthesized from the respective diethyl [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates 5 via opening the aziridine ring with trimethylsilyl azide (TMSN3) followed by hydrogenolysis in the presence of di-tert-butyl dicarbonate (Boc2O). [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1R,2R,1'S)-5a and (1S,2S,1'R)-5c were smoothly transformed into diethyl 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates (1R,2R,1'S)-9a and (1S,2S,1'R)-9c, respectively by the opening of the aziridine ring with acetic acid. Transformations of [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1S,2R,1'S)-5b and (1R,2S,1'R)-5d into diethyl 3-acetoxy-1-benzylamino-2-[(1-phenylethyl)amino]propylphosphonates (1S,2R,1'S)-9b and (1R,2S,1'R)-9d were accompanied by the formation of ethyl {1-(N-benzylacetamido)-3-hydroxy-2-[(1-phenylethyl)amino]propyl}phosphonate (1S,2R,1'S)-10b and (1R,2S,1'R)-10d and 3-(N-benzylacetamido)-4-[N-(1-phenylethyl)]amino-1,2-oxaphospholane (3S,4R,1'S)-11b and (3R,4S,1'R)-11d as side products. Diethyl (1R,2R)-, (1S,2S)-, (1S,2R)- and (1R,2S)-3-acetoxy-1,2-di(N-tert-butoxycarbonylamino)propylphosphonates 7a-7d were obtained from the respective 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates 9a-9d by hydrogenolysis in the presence of Boc2O.

Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides.

Homonucleoside analogues cis-16 and trans-17 having a (5-methoxycarbonyl)isoxazolidine framework were synthesized via the 1,3-dipolar cycloaddition of nucleobase-derived nitrones with methyl acrylate. Hydrogenolysis of the isoxazolidines containing thymine, dihydrouracil, theophylline and adenine moieties efficiently led to the formation of the respective γ-lactam analogues. γ-Lactam analogues having 5-bromouracil and 5-chlorouracil fragments were synthesized by treatment of uracil-containing γ-lactams with NBS and NCS. Isoxazolidine and γ-lactam analogues of homonucleosides obtained herein were evaluated for activity against a broad range of DNA and RNA viruses. None of the compounds that were tested exhibited antiviral or cytotoxic activity at concentrations up to 100 µM. The cytostatic activities of all compounds toward nine cancerous cell lines was tested. γ-Lactams trans-15e (Cl-Ura) and cis-15h (Theo) appeared the most active toward pancreatic adenocarcinoma cells (Capan-1), showing IC50 values 21.5 and 18.2 µM, respectively. Isoxazolidine cis-15e (Cl-Ura) inhibited the proliferation of colorectal carcinoma (HCT-116).

Synthesis and Neuroprotective Properties of N-Substituted C-Dialkoxyphosphorylated Nitrones.

Herein, we report the synthesis and neuroprotective power of some N-substituted C-(dialkoxy)phosphorylated nitrones 4a-g, by studying their ability to increase the cell viability, as well as their capacity to reduce necrosis and apoptosis. We have identified (Z)-N-tert-butyl-1-(diethoxyphosphoryl)methanimine oxide (4e) as the most potent, nontoxic, and neuroprotective agent, with a high activity against neuronal necrotic cell death, a result that correlates very well with its great capacity for the inhibition of the superoxide production (72%), as well as with the inhibition of lipid peroxidation (62%), and the 5-lipoxygenase activity (45%) at 100 µM concentrations. Thus, nitrone 4e could be a convenient promising compound for further investigation.

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds.

Since Garner's aldehyde has several drawbacks, first of all is prone to racemization, alternative three-carbon chirons would be of great value in enantioselective syntheses of natural compounds and/or drugs. This review article summarizes applications of N-(1-phenylethyl)aziridine-2-carboxylates, -carbaldehydes and -methanols in syntheses of approved drugs and potential medications as well as of natural products mostly alkaloids but also sphingoids and ceramides and their 1- and 3-deoxy analogues and several hydroxy amino acids and their precursors. Designed strategies provided new procedures to several drugs and alternative approaches to natural products and proved efficiency of a 2-substituted N-(1-phenylethyl)aziridine framework as chiron bearing a chiral auxiliary.

Synthesis of nonracemic hydroxyglutamic acids.

Glutamic acid is involved in several cellular processes though its role as the neurotransmitter is best recognized. For detailed studies of interactions with receptors a number of structural analogues of glutamic acid are required to map their active sides. This review article summarizes syntheses of nonracemic hydroxyglutamic acid analogues equipped with functional groups capable for the formation of additional hydrogen bonds, both as donors and acceptors. The majority of synthetic strategies starts from natural products and relies on application of chirons having the required configuration at the carbon atom bonded to nitrogen (e.g., serine, glutamic and pyroglutamic acids, proline and 4-hydroxyproline). Since various hydroxyglutamic acids were identified as components of complex natural products, syntheses of orthogonally protected derivatives of hydroxyglutamic acids are also covered.

Synthesis and antimicrobial activity of novel 1,2,3-triazole-conjugates of quinazolin-4-ones.

A novel series of diethyl{4-[(4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates 9aa-aj and their respective derivatives substituted at C6 of the quinazolinone moiety with a bromine atom (9ba-bj) or a nitro group (9ca-cj) were synthesized and assessed for the antibacterial activity toward selected Gram-positive and Gram-negative bacteria. Their antifungal activity was also screened. Compound 9ac was found to be the most active against Staphylococcus aureus ATCC 6535 (MIC 0.625 mg/mL, MBC 1.25 mg/mL), phosphonates 9ab-ai showed promising activity against Enterococcus faecalis ATCC 29212 (MIC = 0.625 mg/mL, MBC = 1.25 mg/mL), while compounds 9ac-j appeared the most active toward Pseudomonas aeruginosa ATCC 27853 (MIC = 0.625 mg/mL, MBC = 1.25 mg/mL). Antifungal assays of compounds 9aa-aj, 9ba-bj, and 9ca-cj were conducted on Candida albicans ATCC 10231 and Aspergillus brasiliensis ATCC 16404 and revealed noticeable activity of 9aa-aj (MIC = 1.25 mg/mL).

Acyclic nucleoside phosphonates containing the amide bond: hydroxy derivatives.

ABSTRACT: To study the influence of a linker rigidity and changes in donor-acceptor properties, three series of nucleotide analogs containing a P-X-HN-C(O)- residue (X=CH(OH)CH2, CH(OH)CH2CH2, CH2CH(OH)CH2) as a replacement for the P-CH2-O-CHR- fragment in acyclic nucleoside phosphonates, e.g., adefovir, cidofovir, were synthesized. EDC proved to provide good yields of the analogs from the respective ω-amino-1- or -2-hydroxyalkylphosphonates and nucleobase-derived acetic acids. New phosphorus-nucleobase linkers are characterized by two fragments of the restricted rotation within amide bonds and in four-atom units (P-CH(OH)-CH2-N, P-CH(OH)-CH2-C and P-CH2-CH(OH)-C) in which antiperiplanar disposition of P and N/C atoms was deduced from 1H and 13C NMR spectral data. The synthesized analogs P-X-HNC(O)-CH2B [X=CH(OH)CH2, CH(OH)CH2CH2, CH2CH(OH)CH2] appeared inactive in antiviral assays on a wide variety of DNA and RNA viruses at concentrations up to 100 µM, while two phosphonates showed cytostatic activity towards myeloid leukemia (K-562) and multiple myeloma cells (MM.1S) with IC50 of 28.8 and 40.7 µM, respectively.