Synthetic applications of the Cannizzaro reaction.

The Cannizzaro reaction has emerged as a versatile synthetic tool for the construction of functionalized molecules. Dating back to the 19th century, this reaction, though initially used for the synthesis of an alcohol and acid functionality from aldehydes, has henceforth proven useful to generate diverse molecular entities using both intermolecular and intramolecular synthetic strategies. Immense applications in the synthesis of hydroxy acids and esters, heterocycles, fused carbocycles, natural products, and others with broad substrate scope have raised profound interest from methodological and synthetic standpoints. The ongoing development of reagents, solvents, and technologies for the Cannizzaro reaction reflects the broader trend in organic synthesis towards more sustainable and efficient practices. The focus of this review is to highlight some recent advances in synthetic strategies and applications of the Cannizzaro reaction towards the synthesis of potentially useful molecules.

Synthesis of Antiepileptic Drug (R)-Lacosamide and Chronic Pain Reliever (S)-Lacosamide from Chiral Glycine Enolate Equivalent.

A short enantioselective and azide-free synthesis of antiepileptic drug (R)-lacosamide and pain reliever (S)-lacosamide on a large scale has been articulated from an uncommon chiral synthon "glycine enolate equivalent of 4-benzyl-N-glycinyl oxazolidinone". Evans' asymmetric alkylation using N-(N-Boc-glycinyl) oxazolidinone was standardized to ensure the stereoselective formation of (Z)-enolate for a diastereofacial selection in the C-alkylation process of chiral glycine enolate equivalent with different alkyl halides such as methyl iodide, methoxymethyl chloride, benzyl bromide, p-NO2C6H4CH2Br, allyl bromide, and p-OCH3C6H4CH2Br in the presence of lithium diisopropyl amide at -78 °C in THF. This optimized asymmetric C-alkylation method with methoxymethyl chloride on lithium-mediated (Z)-enolate of (4S/4R)-4-benzyl-N-glycinyl oxazolidinones was extended following other subsequent reactions to produce the final lacosamides with no racemization in ∼36 to 45% overall yields from commercially available 4-benzyl-2-oxazolidinone and N-Boc-glycine.

Antibacterial Efficacies of Nanostructured Aminoglycosides.

The widespread use of broad-spectrum aminoglycoside antibiotics is restricted from various clinical applications due to the emergence of bacterial resistance and the adverse effects such as ototoxicity and nephrotoxicity. The intensive applicability of nanoparticles in modern medicinal chemistry has gained the interest of researchers for modification of aminoglycosides as nanoconjugates either via covalent conjugation or physical interactions to alleviate their undesirable effects and bacterial resistance. In this context, various carbohydrates, polymers, lipids, silver, gold, and silica-attached aminoglycoside nanoparticles have been reported with improvements in physicochemical properties, bioavailability, and biocompatibility in physiological medium. Overall, this review encompassed the synthesis of nanostructured aminoglycosides and their applications in the development of new antibacterial therapeutics.

Polyurethane-functionalized starch nanocrystals as anti-tuberculosis drug carrier.

Studies related to loading ability and delivery of clinically used first-line anti-tuberculosis drugs (ATDs) such as isoniazid, rifampicin, pyrazinamide and streptomycin on the surface of starch-derived bulk and nanopolyurethanes (SBPUs and SNPUs) as drug delivery systems (DDS) have been focused to minimise or remove the drug-associated adverse effects. The efficiencies of nanopolyurethanes obtained from the differently substituted cyclic aliphatic and aromatic isocyanates have been studied for drug loading and release purposes. Different advanced instrumental techniques analysed the structural and morphological properties, thermal stability and crystallinity of the starch nanopolyurethans. Average particle sizes ranging from 27.35-42.38 nm to 126.89-218.60 nm for starch nanopolyurethans, SNPU3i and SNPU4i, respectively, were determined by high-resolution transmission electron microscopy. Similarly, the loading efficiency of ATDs to the surfaces of SNPUs and SBPUs was observed in the range of 60-97% while ATDs-loaded SNPUs showed a sustainable release profile for all ATDs except for streptomycin. However, most SBPUs provided burst-release for all the above-mentioned ATDs in pH-dependent studies. The anti-tuberculosis assay against the Mycobacterium tuberculosis H37Rv strain revealed that streptomycin-loaded SNPU4i and isoniazid-loaded SNPU7i are approximately 42 and 7 times more active than the native streptomycin and isoniazid, respectively.

First-line anti-tubercutilosis drugs-loaded starch nanocrystals for combating the threat of M. tuberculosis H37Rv strain.

Nanoparticles-based drug delivery is at the forefront in the field of pharmaceutical and medicinal research to eradicate or alleviate the associated impediments, such as prolonged treatment time, high doses, toxicity and resistance problem of anti-tuberculosis drugs for the treatment of age-old tuberculosis disease. Herein, the first-line anti-tuberculosis drugs were loaded into the biodegradable starch nanocrystals and native starch to improve the therapeutic profile addressing the existing issues related to conventional drugs. The loading performance of anti-tuberculosis drugs with starch nanocrystals and native starch was found in the range of 65-95%. According to the release study, the native starch was not appropriate, however, the starch nanocrystals demonstrated sustained release drug delivery for isoniazid and pyrazinamide ranging from 50 to 93% for 24 h; the burst release for streptomycin was reported at pH 2 in 6.5 h while only 14% rifampicin was released at pH 8 buffer. An anti-mycobacterium analysis of strain H37Rv showed that minimum inhibition concentration of starch nanocrystals loaded with isoniazid and pyrazinamide (0.033 µg/mL and 1.25 µg/mL, respectively) were more effective than the parent isoniazid (0.2 µg/mL) and pyrazinamide (25.0 µg/mL) at pH 5.5.

5'-Hydroxymethyl fluorescein: A colorimetric chemosensor for naked-eye sensing of cyanide ion in a biological fluid.

A two-step synthetic method to prepare a highly sensitive and selective chemosensor 5'-hydroxymethyl fluorescein (5'-HMF) is described herein. This sensor was explored as a colorimetric sensor for naked-eye detection of cyanide ion in the biological fluid as well as in organic and aqueous media. The addition of cyanide ion to 5'-HMF resulted in a rapid change in color in aqueous medium from light green to dark fluorescent green, and in acetonitrile from light pink to purple. A significant bathochromic shift in the absorption spectra enables cyanide ion to be detected by naked eyes in water and acetonitrile without any interference of the competing anions such as, AcO-, F- and SCN- in aqueous solution. Using the 1HNMR titration experiments and Job's plot from absorbance spectroscopy, the interaction of CN- ion with 5'-HMF has been investigated and binding stoichiometry was found to be 1:2 (5'-HMF to CN-). The limit of detection (LOD) of the sensor for CN- was 3.68 µM in water with a linearity (R2 = 0.9923) in the range of 0.50 to 30.0 µM concentration assuming 1:2 (5'-HMF to CN-) binding stoichiometry. In addition, the sensor 5'-HMF sensed the CN- ion in human saliva with the LOD as 7.0 µM in aq. medium.

Mechanochemical synthesis of fluorescein-based receptor for CN- ion detection in aqueous solution and cigarette smoke residue.

A facile green method for the mechanochemical synthesis of Schiff base phenylhydrazono-N-methylene fluorescein (PHMF) with 95% yields has been established. The synthesized receptor assists in the naked-eye detection of CN- ions in organic and aqueous media, and F- ions in acetonitrile over a series of anions with a color transfer from colorless to pink. A redshift of 160 nm of PHMF-CN- complex in the absorbance spectrum and a turn-on response in the fluorescence spectrum were observed, respectively, at λmax 345 to 515 and 519 nm. A strong interaction of PHMF with CN- and F- ions forming a 1:3 binding stoichiometry has been noted in this study. In an aqueous medium for CN- ion, the lower limit of detection (LOD) is defined as 9.204 nM, which is quite better in terms of sensitivity. In addition, PHMF's paper-strip sensor for rapid real-time CN- ion sensing was found to be sufficiently sensitive to successfully detect CN- ion in water and a solid state, resulting in a portable device for detecting cyanide ions. In acetonitrile, the receptor's ability to detect CN- ion in cigarette smoke residue was also satisfactorily achieved. Graphical Abstract.

Mechanochemical Synthesis of a Fluorescein-Based Sensor for the Selective Detection and Removal of Hg2+ Ions in Industrial Effluents.

Environmentally benign mechanochemistry-assisted high-yielding synthesis of fluorescein-phenylalaninol (FPA) conjugates as a Schiff base receptor is reported herein. This newly synthesized fluorescent probe is found to be most exciting and efficient because of its simultaneous detection and removal of mercury ions (Hg2+) in aqueous medium and industrial effluents through precipitate formation. The receptor successfully worked as a chemosensor in selectively sensing the Hg2+ ion through the rapid transition from yellow to pink in the colorimetric as well as quenching of fluorescence intensity in the fluorometric assay. The removal of mercury ions was confirmed by the inductively coupled plasma analysis of the supernatant. The lower detection limit of Hg2+ ions for the receptor FPA is 1.65 and 0.34 µM as determined through absorption and fluorescence spectroscopic methods, respectively. The high removal efficiency (∼98%) of the mercury ions is promising and could be achieved via the formation of the complex in a 1:1 stoichiometric ratio of receptor to Hg2+ ions. Furthermore, this probe may be a practical alternative for use in a paper-based portable device for achieving on-site detection of mercury ions in solid, solution, and vapor phases.

Nascent-HBr-Catalyzed Removal of Orthogonal Protecting Groups in Aqueous Surfactants.

Organic reactions in the aqueous environment have recently emerged as a promising research area. The generation of nascent-HBr from the slow hydrolysis of the dispersed catalyst, benzyl bromide, with the interior water present in the hydrophobic core of the confined micellar medium in aqueous surfactant is described for the first time. The sustained-release nascent-HBr enabled the chemoselective cleavages of acid-sensitive orthogonal functionalities present in carbohydrates, amino alcohols, and hydroxylated acyclic compounds in good to excellent yields.

Insights of synthetic analogues of anti-leprosy agents.

Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leadingcause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.

A role for ultrasound in the fabrication of carbohydrate-supported nanomaterials.

Nowadays, sonication is a well-known technique for the fabrication and surface modification of nanomaterials with various sizes, shapes, and chemical and physical properties. In addition to conducting catalyst-mediated chemical reactions and enhancing medicinal properties, such as antibacterial and antifungal activities, nanoparticles made from biodegradable and biocompatible carbohydrate coatings and glycosidic frameworks offer exciting opportunities for the development of biomaterials, optical sensors, packaging materials, agricultural products, and food. This review article discusses the synthesis of carbohydrate-coated nanoparticles by ultrasound radiation as well as the many applications of these nanoparticles.

Potential effect of ultrasound on carbohydrates.

The use of ultrasound has emerged as one of the most useful alternative energy sources for the synthesis of carbohydrate-derived biologically and pharmaceutically potential compounds. Spectacular advances have been made in the field of sonication-assisted organic reactions, which are known for producing superior yields, enhanced reactivity of the reactant, improved stereoselectivity, and shortened reaction times. Orthogonal protection-deprotection reactions and/or modification and manipulation of functional groups in carbohydrates are common synthetic steps in carbohydrate chemistry. These reaction steps can be driven by the ultrasonic energy generated by acoustic cavitation via the formation and subsequent collapse of ultrasound-induced bubbles. The ultrasound-assisted synthesis of differently functionalised monosaccharides is useful in a wide variety of applications of carbohydrate chemistry such as the glycosylation of oligosaccharides, one pot domino reactions, thioglycoside syntheses, azidoglycoside syntheses, 1,3-dipolar cycloaddition reactions, and syntheses of natural products. This review article covers ultrasound-mediated reactions on carbohydrates that have been described in the literature since 2000.

Synthesis and antibacterial activities of amphiphilic neomycin B-based bilipid conjugates and fluorinated neomycin B-based lipids.

Investigating the effect of lipid hydrophobicity on the activity of amphiphilic neomycin B conjugates, six polycationic amphiphiles (PAs) were created. Four of the new compounds incorporated either palmitic or arachidic di-lipid lysine tails, while two had single fluorinated undecanoic acid tails. The basicity of half of the compounds was increased through the incorporation of six guanidine moieties, in order to assess the effect of base strength on antimicrobial activity. A panel of ten bacteria was used for the testing, with seven strains obtained from the American Type Culture Collection series and three clinical isolates from Canadian Intensive Care Units. When compared to previous results with hydrocarbon monolipids the PAs all compounds were found to have reduced activity, though the hemolytic activity of the compounds with fluorinated tails was sharply reduced, with only a moderate reduction in antimicrobial activity.

Antibacterial activity of amphiphilic tobramycin.

Amphiphilic aminoglycoside antimicrobials are an emerging class of new antibacterial agents with novel modes of action. Previous studies have shown that amphiphilic neomycin-B and kanamycin-A analogs restore potent antibacterial activity against Gram-positive neomycin-B- and kanamycin-A-resistant organisms. In this paper, we investigated the antibacterial properties of a series of amphiphilic tobramycin analogs. We prepared tobramycin-lipid conjugates, as well as tobramycin-peptide triazole conjugates, and studied their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains, including isolates obtained from Canadian hospitals. Our results demonstrate that the antibacterial activity of amphiphilic tobramycin is greatly affected by the length and nature of the hydrophobic lipid tail, whereas the nature of the polycationic headgroup or the number of cationic charges appear to be less important. Replacement of the hydrophobic tail by a fluorinated lipid confers good activity against two Pseudomonas strains and reduces hemolytic activity. However, susceptibility studies in the presence of bovine serum albumin indicate that all amphiphilic tobramycin analogs are strongly protein-bound, leading to a typical four- to eight-fold increase in MIC.

Chemoenzymatic synthesis of uridine diphosphate-GlcNAc and uridine diphosphate-GalNAc analogs for the preparation of unnatural glycosaminoglycans.

Eight N-acetylglucosamine-1-phosphate and N-acetylgalactosamine-1-phosphate analogs have been synthesized chemically and were tested for their recognition by the GlmU uridyltransferase enzyme. Among these, only substrates that have an amide linkage to the C-2 nitrogen were transferred by GlmU to afford their corresponding uridine diphosphate(UDP)-sugar nucleotides. Resin-immobilized GlmU showed comparable activity to nonimmobilized GlmU and provides a more facile final step in the synthesis of an unnatural UDP-donor. The synthesized unnatural UDP-donors were tested for their activity as substrates for glycosyltransferases in the preparation of unnatural glycosaminoglycans in vitro. A subset of these analogs was useful as donors, increasing the synthetic repertoire for these medically important polysaccharides.

Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates.

Amphiphilic lysine-ligated neomycin B building blocks were prepared by reductive amination of a protected C5″-modified neomycin B-based aldehyde and side chain-unprotected lysine or lysine-containing peptides. It was demonstrated that a suitably protected lysine-ligated neomycin B conjugate (NeoK) serves as a building block for peptide synthesis, enabling incorporation of aminoglycoside binding sites into peptides. Antibacterial testing of three amphiphilic lysine-ligated neomycin B conjugates against a representative panel of Gram-positive and Gram-negative strains demonstrates that C5″-modified neomycin-lysine conjugate retains antibacterial activity. However, in most cases the lysine-ligated neomycin B analogs display reduced potency against Gram-positive strains when compared to unmodified neomycin B or unligated peptide. An exception is MRSA where an eightfold enhancement was observed. When compared to unmodified neomycin B, the prepared lysine-neomycin conjugates exhibited a 4-8-fold enhanced Gram-negative activity against Pseudomonas aeruginosa and up to 12-fold enhanced activity was observed when compared to unligated reference peptides.

Design and synthesis of unnatural heparosan and chondroitin building blocks.

Triazole linked heparosan and chondroitin disaccharide and tetrasaccharide building blocks were synthesized in a stereoselective manner by applying a very efficient copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction of appropriately substituted azido-glucuronic acid and propargyluted N-acetyl glucosamine and N-acetyl galactosamine derivative, respectively. The resulting suitably substituted tetrasaccharide analogues can be easily converted into azide and alkyne unit for further synthesis of higher oligosaccharide analogues.

Evaluation of amphiphilic aminoglycoside-peptide triazole conjugates as antibacterial agents.

The solid- and solution-phase synthesis of amphiphilic aminoglycoside-peptide triazole conjugates (APTCs) accessed by copper(I)-catalyzed 1,3-dipolar cycloaddition reaction between a hydrophobic and ultrashort peptide-based alkyne and a neomycin B- or kanamycin A-derived azide is presented. Antibacterial evaluation demonstrates that the antibacterial potency is affected by the nature of the peptide component. Several APTCs exhibit superior activity against neomycin B- and kanamycin A-resistant strains when compared to their parent aminoglycoside while displaying reduced activity against neomycin B- and kanamycin A-susceptible strains.

Antibacterial activities of aminoglycoside antibiotics-derived cationic amphiphiles. Polyol-modified neomycin B-, kanamycin A-, amikacin-, and neamine-based amphiphiles with potent broad spectrum antibacterial activity.

Cationic amphiphiles containing multiple positively charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. We have prepared a novel class of cationic amphiphiles termed aminoglycoside antibiotics-derived amphiphiles in which the polyol scaffold of the aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. Our results show that the nature of the polyol modification as well as the nature of the aminoglycoside antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles containing unsubstituted aromatic rings. These analogues exhibit up to 256-fold enhanced antibacterial activity against resistant strains when compared to neomycin B while retaining most of their activity against neomycin B-susceptible strains.

Antibacterial activity of guanidinylated neomycin B- and kanamycin A-derived amphiphilic lipid conjugates.

OBJECTIVES: Neomycin B exhibits poor antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, while kanamycin A shows weak activity against MRSA, methicillin-resistant Staphylococcus epidermidis (MRSE) and P. aeruginosa. The main purpose of this work was to study whether lipid conjugation of guanidinylated neomycin B- and kanamycin A-derived cationic headgroups could restore antibacterial activity against neomycin B- and kanamycin A-resistant strains, while retaining antibacterial activity against non-resistant strains. METHODS: Seven polyguanidinylated neomycin B-lipids differing in the nature of the lipid tail and two cationic kanamycin A-lipids were prepared, and their in vitro activity was assessed against a variety of neomycin B- and kanamycin A-resistant and neomycin B- and kanamycin A-non-resistant Gram-positive and Gram-negative strains. RESULTS: Conjugation of neomycin B- and kanamycin A-derived polyamine or polyguanidinylated headgroups to hydrophobic C16 or C20 lipid tails restored the anti-MRSA activity of both aminoglycosides and the anti-MRSE activity of kanamycin A. Polyguanidinylation of the neomycin B-derived headgroup lowers the hydrophobic requirement of the lipid tail segment to provide broad-spectrum antibacterial activity from C16 to C12. Moreover, guanidinylation of the polycationic headgroup in neomycin B-derived cationic lipids enhances antibacterial activity against a neomycin B-, kanamycin A- and gentamicin-resistant P. aeruginosa strain, and reduces haemolytic activity. CONCLUSIONS: These findings suggest that lipid conjugation of neomycin B- and kanamycin A-derived cationic lipids provides a general tool to enhance the antibacterial activity of these two aminoglycosides against resistant strains.