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 and 5-substituted-3-(dibenzyloxyphosphoryl)isoxazolidines - were synthesized by the 1,3-dipolar cycloaddition reaction of -benzyl--(dibenzyloxyphosphoryl)nitrone and selected -allyl--benzylquinazoline-2,4-diones. All the obtained -isoxazolidines - and the samples enriched in respective -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).

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

The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel -benzyl-2-[4-(aryl)-1-1,2,3-triazol-1-yl]ethan-1-imine oxides - are reported herein. The nitrones - 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).

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

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, -protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl ()- and ()-2-(-Boc-amino)propylphosphonates were obtained via direct regiospecific hydrogenolysis of the respective enantiomer of ()- and ()--Boc-(aziridin-2-yl)methylphosphonates. N-Boc-protected ()- and ()-2,3-diaminopropylphosphonates were synthesized from ()- and ()--Bn-(aziridin-2-yl)methylphosphonates via a regiospecific ring-opening reaction with neat trimethylsilyl azide and subsequent reduction of ()- and ()-2-(-Boc-amino)-3-azidopropylphosphonates using triphenylphosphine.

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 -(2-(4-aryl-1-1,2,3-triazol-1-yl)ethylidene)methanamine oxides - and -(2-(4-aryl)-1-1,2,3-triazol-1-yl)ethylidene)-2-methylpropan-2-amine oxides -, bearing an -methyl, and an -butyl substituent, respectively, at the nitrogen of the nitrone motif. Nitrones and 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.

Design and synthesis of a new series of hybrids of functionalised N-[(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 N-propargylquinazoline-2,4-diones 26aa-26ag, 26ba-26bg, 27aa-27ad and 27ba-27bd was applied for the syntheses of the designed compounds.

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

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 -(diethoxyphosphonyl)nitrones with -allyl--benzylquinazoline-2,4-diones produced mixtures of diastereoisomeric 3-(diethoxyphosphonyl)isoxazolidines with a -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 EC values in the range of 12.

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 ()- and ()-1-(-Boc-amino)-3-oxopropylphosphonates with diethyl phosphite, separation of diastereoisomeric [1-(-Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates as -protected esters, followed by their hydrolysis to the enantiomeric phosphonic acids. The absolute configuration of the enantiomeric phosphonates was established by comparing the P NMR chemical shifts of respective ()--methylmandelic acid esters obtained from respective pairs of - and -[1-(-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 -. The neuroprotective properties of nitrones, -, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, -, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone () and are similar to N-acetyl-L-cysteine (), a well-known antioxidant and neuroprotective agent.

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

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 - and -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.

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 -benzyl--(diethoxyphosphoryl)nitrone to -1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. ,-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from ,-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of ,-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into ,-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.

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(--butoxycarbonylamino)propylphosphonate were synthesized from the respective diethyl [-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates via opening the aziridine ring with trimethylsilyl azide (TMSN) followed by hydrogenolysis in the presence of di--butyl dicarbonate (BocO). [-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1,2,1')- and (1,2,1')- were smoothly transformed into diethyl 3-acetoxy-1-benzylamino-2-[-(1-phenylethyl)amino]propylphosphonates (1,2,1')- and (1,2,1')-, respectively by the opening of the aziridine ring with acetic acid. Transformations of [-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1,2,1')- and (1,2,1')- into diethyl 3-acetoxy-1-benzylamino-2-[(1-phenylethyl)amino]propylphosphonates (1,2,1')- and (1,2,1')- were accompanied by the formation of ethyl {1-(-benzylacetamido)-3-hydroxy-2-[(1-phenylethyl)amino]propyl}phosphonate (1,2,1')- and (1,2,1')- and 3-(-benzylacetamido)-4-[-(1-phenylethyl)]amino-1,2-oxaphospholane (3,4,1')- and (3,4,1')- as side products.

Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides.

Homonucleoside analogues - and - 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.

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

Herein, we report the synthesis and neuroprotective power of some N-substituted -(dialkoxy)phosphorylated nitrones -, by studying their ability to increase the cell viability, as well as their capacity to reduce necrosis and apoptosis. We have identified ()---butyl-1-(diethoxyphosphoryl)methanimine oxide () 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 could be a convenient promising compound for further investigation.

-(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 -(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 -(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.

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.

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)CH, CH(OH)CHCH, CHCH(OH)CH) as a replacement for the P-CH-O-CHR- fragment in acyclic nucleoside phosphonates, e.g., adefovir, cidofovir, were synthesized.

Novel isoxazolidine analogues of homonucleosides and homonucleotides.

Isoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl- and vinyloxymethyl- and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e.

Acyclic nucleoside phosphonates containing the amide bond.

Abstract: To study the influence of a linker rigidity and donor-acceptor properties, the P-CH-- fragment in acyclic nucleoside phosphonates (e.g., acyclovir, tenofovir) was replaced by the P-CH-- residue.

Synthesis and the Biological Activity of Phosphonylated 1,2,3-Triazolenaphthalimide Conjugates.

A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1-benzo[]isoquinolin-2(3)-yl)-methyl]-1-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized. All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses and several of them showed potency against varicella-zoster virus (VZV) [EC (50% effective concentration) = 27.6-91.

Synthesis, anti-varicella-zoster virus and anti-cytomegalovirus activity of quinazoline-2,4-diones containing isoxazolidine and phosphonate substructures.

Cycloadditions of N-substituted C-(diethoxyphosphoryl)nitrones to N-allylated quinazoline-2,4-diones functionalized at N3 with substituted benzoyl or benzyl groups proceeded with moderate to good diastereoselectivities (d.e. 28-68%).