Novel Benzotriazole-β-lactam Derivatives as Antimalarial Agents: Design, Synthesis, Biological Evaluation and Molecular Docking Studies.

Many people around the world suffer from malaria, especially in tropical or subtropical regions. While malaria medications have shown success in treating malaria, there is still a problem with resistance to these drugs. Herein, we designed and synthesized some structurally novel benzotriazole-β-lactams using 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid as a key intermediate.

Synthesis, docking and evaluation of in vitro anti-inflammatory activity of novel morpholine capped β-lactam derivatives.

This study reports the synthesis and biological investigation of three series of novel monocyclic β-lactam derivatives bearing a morpholine ring substituent on the nitrogen. The resulting β-lactam adducts were synthesized via Staudinger's [2 + 2]-ketene-imine cycloaddition reaction. New synthesized products were fully characterized by spectral data and elemental analyses, and then evaluated for anti-inflammatory activity toward human inducible nitric oxide synthase (iNOS) and cytotoxicity toward HepG2 cell line.

Investigations of antiproliferative and antioxidant activity of β-lactam morpholino-1,3,5-triazine hybrids.

This article reports for the first time the synthesis of some novel β-lactam morpholino-1,3,5-triazine hybrids by a [2+2]-cycloaddition reaction of imines 7a-c, 9a-c and 11 with ketenes derived from substituted acetic acids. The reaction was totally diastereoselective, leading exclusively to the formation of cis-β-lactams 8a-l, 10a-f and 12a-c. The synthesized compounds were tested for activity towards SW1116, MCF-7 and HepG2 cancer cell lines and non-cancerous HEK-293 cell line by MTT assay.

Anti-Methicillin-Resistant Nanoantibiotics.

Nanoparticle-based antibiotic constructs have become a popular area of investigation in the biomedical sciences. Much of this work has pertained to human diseases, largely in the cancer therapy arena. However, considerable research has also been devoted to the nanochemistry for controlling infectious diseases.

Three-component synthesis of chromeno β-lactam hybrids for inflammation and cancer screening.

Highly diastereoselective synthesis of chromeno β-lactam hybrids was achieved by an efficient one-pot three-component reaction. With this procedure, the desired β-lactam products were obtained in good yields and with exclusive cis stereoselection, by combining a variety of benzaldehydes, malononitrile, and either 5,5-dimethylcyclohexane-1,3-dione or 4-hydroxycoumarin in the presence of 1,4-diazabicyclo [2.2.

Synthesis and biological evaluation of some novel diastereoselective benzothiazole β-lactam conjugates.

Highly diastereoselective synthesis of some novel benzothiazole-substituted β-lactam hybrids was achieved starting from (benzo[d]thiazol-2-yl)phenol as an available precursor. This is the first time (benzo[d]thiazol-2-yl)phenoxyacetic acid has been used as ketene source in synthesizing monocyclic 2-azetidinones. These compounds were evaluated for their antimicrobial activities against a large panel of Gram-positive and Gram-negative bacterial strains and moderate activities were encountered.

Studies on the antimicrobial properties of N-acylated ciprofloxacins.

Fluoroquinolone antibiotics have been a mainstay in the treatment of bacterial diseases. The most notable representative, ciprofloxacin, possesses potent antimicrobial activity; however, a rise in resistance to this agent necessitates development of novel derivatives to prolong the clinical lifespan of these antibiotics. Herein we have synthesized and analyzed the antimicrobial properties of a library of N-acylated ciprofloxacin analogues.

Attenuating the size and molecular carrier capabilities of polyacrylate nanoparticles by a hydrophobic fluorine effect.

This study investigates the effect of introducing alkyl chain fluorination on the properties of polyacrylate nanoparticles prepared in aqueous solution by emulsion polymerization. For this, 2,2,3,3,4,4,4-heptafluorobutyl acrylate (1) and methyl trifluoroacrylate (2) were tested as monomers as a means to prepare fluorinated polyacrylate nanoparticles to evaluate how side chain fluorination may affect nanoparticle size and drug carrier properties. Our results show that as fluorine content within the polyacrylate matrix increases, the size of the nanoparticle systematically diminishes, from 45 nm (for nanoparticles containing no fluoroacrylate) to ~7 nm (for nanoparticles constructed solely of fluoroacrylate).

Epigenetic tailoring for the production of anti-infective cytosporones from the marine fungus Leucostoma persoonii.

Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones.

Unlocking the binding and reaction mechanism of hydroxyurea substrates as biological nitric oxide donors.

Hydroxyurea is the only FDA approved treatment of sickle cell disease. It is believed that the primary mechanism of action is associated with the pharmacological elevation of nitric oxide in the blood; however, the exact details of this are still unclear. In the current work, we investigate the atomic level details of this process using a combination of flexible-ligand/flexible-receptor virtual screening coupled with energetic analysis that decomposes interaction energies.

CNS and antimalarial activity of synthetic meridianin and psammopemmin analogs.

The marine invertebrate-derived meridianin A, the originally proposed structure for psammopemmin A, and several related 3-pyrimidylindole analogs were synthesized and subsequently investigated for central nervous system, antimalarial, and cytotoxic activity. A Suzuki coupling of an indoleborate ester to the pyrimidine electrophile was utilized to form the natural product and derivatives thereof. The 3-pyrimidineindoles were found to prevent radioligand binding to several CNS receptors and transporters, most notably, serotonin receptors (<0.

A convenient method to prepare emulsified polyacrylate nanoparticles from powders [corrected] for drug delivery applications.

We describe a method to obtain purified, polyacrylate nanoparticles in a homogeneous powdered form that can be readily reconstituted in aqueous media for in vivo applications. Polyacrylate-based nanoparticles can be easily prepared by emulsion polymerization using a 7:3 mixture of butyl acrylate and styrene in water containing sodium dodecyl sulfate as a surfactant and potassium persulfate as a water-soluble radical initiator. The resulting emulsions contain nanoparticles measuring 40-50 nm in diameter with uniform morphology, and can be purified by centrifugation and dialysis to remove larger coagulants as well as residual surfactant and monomers associated with toxicity.

Poly(vinyl benzoate) nanoparticles for molecular delivery: Studies on their preparation and in vitro properties.

The preparation and properties of poly(vinyl benzoate) nanoparticle suspensions as molecular carriers are described for the first time. These nanoparticles can be formed by nanoprecipitation of commercial poly(vinyl benzoate) in water using Pluronic F68 as surfactant, to create spherical nanostructures measuring 200-250nm in diameter. These nanoparticles are stable in phosphate buffer and blood serum, and only slowly degrade in the presence of esterases.

Palmadorins A--C, diterpene glycerides from the antarctic nudibranch Austrodoris kerguelenensis.

The nudibranch Austrodoris kerguelenensis is distributed widely around the Antarctic coast and continental shelves. Earlier collections from McMurdo Sound and the Weddell Sea shelf have afforded a suite of diterpene glyceride esters, a compound class implicated as a chemical defense in nudibranchs. The present chemical investigation of A.

Physical properties and biological activity of poly(butyl acrylate-styrene) nanoparticle emulsions prepared with conventional and polymerizable surfactants.

Unlabelled: Recent efforts in our laboratory have explored the use of polyacrylate nanoparticles in aqueous media as stable emulsions for potential applications in treating drug-resistant bacterial infections. These emulsions are made by emulsion polymerization of acrylated antibiotic compounds in a mixture of butyl acrylate and styrene (7:3 wt/wt) using sodium dodecyl sulfate as a surfactant. Prior work in our group established that the emulsions required purification to remove toxicity associated with extraneous surfactant present in the media.

In vivo studies of polyacrylate nanoparticle emulsions for topical and systemic applications.

We have recently reported on a new nanomedicine containing antibiotic-conjugated polyacrylate nanoparticles, which has shown activity against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and no cytotoxicity toward human dermal cells. The water-based nanoparticle emulsion is capable of solubilizing lipophilic antibiotics for systemic administration, and the nanoparticle drug delivery vehicle has shown protective properties for antibiotics from hydrolytic cleavage by bacterial penicillinases, thus rejuvenating the drug's activity against resistant microbes such as MRSA. Here we report the first in vivo study of this penicillin-conjugated nanoparticle emulsion in determining toxicological responses initiated upon systemic and topical application in a murine model.

Drug delivery approaches to overcome bacterial resistance to beta-lactam antibiotics.

Background: Since its landmark discovery in 1928, penicillin has had a profound impact on the quality of human life. The ability to treat and cure deadly infections and bacterial diseases has forever changed our medical profession and way of life, providing unprecedented relief from pain, suffering, and death due to microbial infection. Penicillin and its many derivatives have dominated the field of antibiotics research and development, while demonstrating unprecedented success as a therapeutic used around the world.

Glycosylated polyacrylate nanoparticles by emulsion polymerization.

A selection of glycosylated polyacrylate nanoparticles has been prepared by radical-initiated emulsion polymerization in aqueous media. Using ethyl acrylate as a co-monomer, carbohydrate acrylates were incorporated into the poly(ethyl acrylate) framework to give stable emulsions of glyconanoparticles with an average particle size of around 40 nm. Using this technique a variety of glyconanoparticles were prepared from 3-O-acryloyl-1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose, 1-O-acryloyl-2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose, 6-O-acryloyl-1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranose, 2-N-acryloyl-1,3,4,6-tetra-O-acetyl-beta-D-glucosamine, 5-O-acryloyl-2,3-isopropylidene-1-methoxy-beta-D-ribofuranose and 4-N-acetyl-5'-O-acryloyl-2',3'-O-isopropylidene cytidine.

Studies on the antifungal properties of N-thiolated beta-lactams.

N-thiolated beta-lactams had previously been shown to have antibacterial activity against a narrow selection of pathogenic bacteria including Staphylococcus aureus and Bacillus anthracis, as well as apoptotic-inducing activity in a variety of human cancer cell lines. We now have found that these lactams also possess antifungal activity against Candida and other fungi by exerting powerful cytostatic effects that disrupt the structural integrity of cytoplasmic membranes. The mode of action and structure-activity trends of these lactams as antifungals parallel that previously seen in our antibacterial studies.

Unsymmetric aryl-alkyl disulfide growth inhibitors of methicillin-resistant Staphylococcus aureus and Bacillus anthracis.

This study describes the antibacterial properties of synthetically produced mixed aryl-alkyl disulfide compounds as a means to control the growth of Staphylococcus aureus and Bacillus anthracis. Some of these compounds exerted strong in vitro bioactivity. Our results indicate that among the 12 different aryl substituents examined, nitrophenyl derivatives provide the strongest antibiotic activities.

Methods for purifying and detoxifying sodium dodecyl sulfate-stabilized polyacrylate nanoparticles.

Recent research in our laboratory has centered on studies of polyacrylate and polyacrylamide nanoparticle emulsions for use in antibiotic delivery. Our goal is to develop these nanoparticle emulsions for treatment of life-threatening bacterial infections such as those caused by methicillin-resistant Staphylococcus aureus. For this intended application it is necessary to ensure that the biological activity of the emulsion is due only to the drug attached to the polymeric chain and not to any extraneous components.

Glyconanobiotics: Novel carbohydrated nanoparticle antibiotics for MRSA and Bacillus anthracis.

This report describes the synthesis and evaluation of glycosylated polyacrylate nanoparticles that have covalently-bound antibiotics within their framework. The requisite glycosylated drug monomers were prepared from one of three known antibiotics, an N-sec-butylthio beta-lactam, ciprofloxacin, and a penicillin, by acylation with 3-O-acryloyl-1,2-O-isopropylidene-5,6 bis((chlorosuccinyl)oxy)-d-glucofuranose (7) or 6-O-acetyl-3-O-acryloyl-1,2-O-isopropylidene-5-(chlorosuccinyl)oxy-alpha-d-glucofuranose (10). These acrylated monomers were subjected to emulsion polymerization in a 7:3 (w:w) mixture of butyl acrylate-styrene in the presence of sodium dodecyl sulfate as surfactant (3 weight %) and potassium persulfate as a radical initiator (1 weight %).

Ecdysteroids from the Antarctic tunicate Synoicum adareanum.

Five new ecdysteroids, hyousterones A-D (2-5) and abeohyousterone (6), have been isolated from the Antarctic tunicate Synoicum adareanum along with the known ecdysteroid diaulusterol B (1). Hyousterones B (3) and D (5) are unusual ecdysteroids in bearing the 14beta-hydroxyl group, and abeohyousterone incorporates the 13(14-->8) abeo steroid skeleton, reflecting a rearrangement of the steroid C/D ring system. Abeohyousterone has moderate cytotoxicity toward several cancer cell lines.

Penicillin-bound polyacrylate nanoparticles: restoring the activity of beta-lactam antibiotics against MRSA.

This report describes the preparation of antibacterially active emulsified polyacrylate nanoparticles in which a penicillin antibiotic is covalently conjugated onto the polymeric framework. These nanoparticles were prepared in water by emulsion polymerization of an acrylated penicillin analogue pre-dissolved in a 7:3 (w:w) mixture of butyl acrylate and styrene in the presence of sodium dodecyl sulfate (surfactant) and potassium persulfate (radical initiator). Dynamic light scattering analysis and atomic force microscopy images show that the emulsions contain nanoparticles of approximately 40 nm in diameter.

Synthesis of 2-oxazolidinones from beta-lactams: stereospecific total synthesis of (-)-cytoxazone and all of its stereoisomers.

The synthetic correlation between two different antibiotic frameworks, the beta-lactams and 2-oxazolidinones, is described for the first time. In this approach, 2-oxazolidinones are prepared in stereomerically pure form from 3-hydroxy beta-lactams by a ring-opening-cyclization isomerization process. Application of this methodology to the total synthesis of the cytokine modulator, (-)-cytoxazone, and its three stereoisomers is demonstrated.