Promising applications of phyto-fabricated silver nanoparticles: Recent trends in biomedicine.

The prospective contribution of phyto-nanotechnology to the synthesis of silver nanomaterials for biomedical purposes is attracting increasing interest across the world. Green synthesis of silver nanoparticles (Ag-NPs) through plants has been extensively examined recently, and it is now seen to be a green and efficient path for future exploitation and development of practical nano-factories. Fabrication of Ag-NPs is the process involves use of plant extracts/phyto-compounds (e.g.alkaloids, terpenoids, flavonoids, and phenolic compounds) to synthesise nanoparticles in more economical and feasible. Several findings concluded that in the field of medicine, Ag-NPs play a major role in pharmacotherapy (infection and cancer). Indeed, they exhibits novel properties but the reason is unclear (except some theoretical interpretation e.g. size, shape and morphology). But recent technological advancements help to address these questions by predicting the unique properties (composition and origin) by characterizing physical, chemical and biological properties. Due to increased list of publications and their application in the field of agriculture, industries and pharmaceuticals, issues relating to toxicity are unavoidable and question of debate. The present reviews aim to find out the role of plant extracts to synthesise Ag-NPs. It provides an overview of various phytocompounds and their role in the field of biomedicine (antibacterial, antioxidant, anticancer, anti-inflammatory etc.). In addition, this review also especially focused on various applications such as role in infection, oxidative stress, application in medical engineering, diagnosis and therapy, medical devices, orthopedics, wound healing and dressings. Additionally, the toxic effects of Ag-NPs in cell culture, tissue of different model organism, type of toxic reactions and regulation implemented to reduce associated risk are discussed critically. Addressing all above explanations, this review focus on the detailed properties of plant mediated Ag-NPs, its impact on biology, medicine and their commercial properties as well as toxicity.

Robust Sub-5 Nanometer bis(Diarylcarbene)-Based Thin Film for Molecular Electronics and Plasmonics.

In miniaturized electronic and optoelectronic circuits, molecular tunnel junctions have attracted enormous research interest due to their small footprint, low power consumption, and rich molecular functions. However, the most popular building blocks used in contemporary molecular tunnel junctions are thiol molecules, which attach to electrode surfaces via a metal-thiolate (MS) bond, showing low stability and usually quick degradation within several days. To pave the way for more widely applicable and stable molecular tunnel junctions, there is a need to develop new molecular anchoring groups. Here, this work demonstrates robust and air-stable molecular tunnel junctions with a sub-5 nanometer bis(diarylcarbene)-based thin film as the tunneling barrier, which anchors to the electrode surface via a AuC bond. The bis(diarylcarbene)-based molecular tunnel junctions exhibit high thermal stability against heating up to 200 °C and long storage lifetime over 5 months in an ambient environment. Both electrical and optical performance of these bis(diarylcarbene)-based molecular junctions are characterized systematically, showing similar behaviors to thiol-based junctions as well as largely improved emission stability. This research highlights the excellent performance of bis(diarylcarbene)-based molecular tunnel junctions, which could be useful for applications in molecular electronics and plasmonics.

Synthesis of fused tetramate-oxazolidine and -imidazolidine derivatives and their antibacterial activity.

A chemoselective route which provides direct access to bicyclic tetramates, making use of Dieckmann cyclisation of functionalised oxazolidines and imidazolidines derived from an aminomalonate, is reported; calculations suggest that the observed chemoselectivity is kinetically controlled and leads to the thermodynamically most stable product. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria, and this activity is maximal in a well-defined region of chemical space (554 < Mw < 722 g mol-1; 5.78 < cLogP < 7.16; 788 < MSA < 972 Å2; 10.3 < rel. PSA < 19.08).

Tetramate derivatives by chemoselective Dieckmann ring closure of allo-phenylserines, and their antibacterial activity.

A general route which provides direct access to substituted bicyclic tetramates, making use of Dieckmann cyclisation of oxazolidine derivatives derived from allo-phenylserines, is reported. Of interest is the high level of diastereoselectivity observed for the N-acylation reaction of oxazolidines and the complete chemoselectivity of their ring closure in the Dieckmann cyclisation. Significantly, the sense of the chemoselectivity is different to earlier reported threo-phenylserine systems, showing the importance of steric bulk around the bicyclic ring system. The derived C7-carboxamidotetramates, but not C7-acyl systems, exhibited potent antibacterial activity against MRSA, with the most active compounds exhibiting well-defined physicochemical and structure-activity properties. This work clearly demonstrates that densely functionalised tetramates are both readily available and may exhibit high levels of antibacterial activity.

Surface modified materials for active capture of enzymes.

The insertion of bis(diarylcarbene)s onto a glass fiber (GF) membrane surface provided an active coating for the direct capture of protein - exemplified by the enzyme, cellulase - through a mild diazonium coupling process which does not require additional coupling agents. Successful cellulase attachment on the surface was demonstrated by the disappearance of diazonium and formation of azo functions in the N 1s high resolution spectra, the appearance of carboxyl group in C 1s spectra, both observed by XPS; the -CO vibrational bond observed by ATR-IR; as well as the observation of fluorescence. Further, five support materials (polystyrene XAD4 bead, polyacrylate MAC3 bead, glass wool, glass fiber membrane, polytetrafluoroethylene membrane) with different morphology and surface chemistry, were examined in detail as supports for cellulase immobilization using this common surface modification protocol. Of interest is that such covalently bound cellulase on modified GF membrane gave both the highest enzyme loading (∼23 mg cellulase per g support), and retained more than 90% of activity after 6 cycles of re-use, compared with substantial loss of enzyme activity for physiosorbed cellulase after 3 cycles. Optimization of the degree of surface grafting and the effectiveness of a spacer between surface and enzyme for enzyme loading and activity were conducted. This work shows that carbene surface modification is a viable strategy for introducing enzymes onto a surface under very mild conditions and retaining a meaningful level of activity, and particularly, using GF membrane as a novel support provides a potential platform for enzyme and protein immobilization.

Tetramate Derivatives by Chemoselective Dieckmann Ring Closure of threo-Phenylserines and Their Antibacterial Activity.

A general route, which provides direct access to substituted bicyclic tetramates, making use of Dieckmann cyclization of oxazolidines derived from threo-arylserines, is reported; the latter were found to be available by an efficient aldol-like reaction of glycine with some substituted benzaldehydes under alkaline conditions. The tetramates were found to release chelated metal cations acquired during chromatographic purification by mild acid wash. Some compounds in the library showed good antibacterial activity against Gram-positive bacteria. Cheminformatic analysis demonstrates that the most active compounds were Ro5-compliant and occupy a narrow region of chemical space, distinct from that occupied by other known antibiotics, with the most potent compounds having 399 < Mw < 530 Da; 3.5 < cLogP < 6.6; 594 < MSA <818 Å2; 9.6 < rel. PSA <13.3%. MIC values were shifted to higher concentrations when tested in the presence of HSA or blood, but was not completely abolished, consistent with a plasma protein binding (PPB) effect.

An Overview of Synthetic Routes of Pharmaceutically Important Pyranopyrazoles.

Pyranopyrazoles are bicyclic nitrogen-containing heterocycles having broadspectrum bioactivities, which may act as anti-cancer, anti-inflammatory, antibacterial, antifungal, insecticidal and molluscicidal agents. Pyranopyrazoles have become an attractive scaffold for the discovery of new drugs due to the diverse range of bioactivities associated with this nucleus. In this review, we have focused on the medicinal importance of pyranopyrazole derivatives and highlighted different routes for the synthesis of pyranopyrazole derivatives using inexpensive and commonly available starting materials.

Tricyclic Fused Lactams by Mukaiyama Cyclisation of Phthalimides and Evaluation of their Biological Activity.

We report that phthalimides may be cyclized using a Mukaiyama-type aldol coupling to give variously substituted fused lactam (1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one) systems. This novel process shows a high level of regioselectivity for o-substituted phthalimides, dictated by steric and electronic factors, but not for m-substituted phthalimides. The initial aldol adduct is prone to elimination, giving 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones, and the initial cyclisation can be conducted in such a way that aldol cyclisation-elimination is achievable in a one-pot approach. The 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones possess cross conjugation and steric effects which significantly influence the reactivity of several functional groups, but conditions suitable for epoxidation, ester hydrolysis and amide formation, and reduction, which provide for ring manipulation, were identified. Many of the derived lactam systems, and especially the eliminated systems, show low solubility, which compromises biological activity, although in some cases, antibacterial and cytotoxic activity was found, and this new class of small molecule provides a useful skeleton for further elaboration and study.

Metal Binding and Its Amelioration in Tetramates.

Metal chelation in tetramates may be ameliorated by changing the ligating group and by steric blocking, which in turn leads to a change in their antibacterial properties; the former was achieved by replacement of an amide with a C-9 C═N bond and the latter by the synthesis of cysteine-derived tetramates with functionalization at the C-6 or C-9 enolic groups. In both cases, the metal-chelating ability was weak, and a loss of antibacterial activity was observed. Tetramate alkylations with an extended tricarbonyl-conjugated system could be achieved under Mitsunobu conditions which led to regioisomers, distinguishable by careful heteronuclear multiple bond coherence correlation and carbonyl carbon chemical shift analysis. C-9 and C-6 O-alkylation were observed but not C-8 O-alkylation for tetramate carboxamides; interestingly, C-7 alkylation with allyl and prenyl derivatives was also observed, and this arose by the rearrangement of initially formed O-alkyl products. Only the C-7 alkylated tetramate derivatives 13a and 13d with no metal-chelating ability demonstrated promising antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), with the most active analogue exhibiting a minimum inhibitory concentration of ≤ 1.95 µg/mL against MRSA, suggesting a mechanism of action independent of metal chelation. Otherwise, modifications at C-6/C-9 of tetramates led to a complete loss of metal-chelating ability, which correlated with the loss of antibacterial activity. This work further confirms that the metal-chelating capability is of fundamental importance in the biological activity of tetramates.

Mediation of metal chelation in cysteine-derived tetramate systems.

A study of bicyclic tetramates modified with a bulky ester, which leads to steric hindrance of distal chelating atoms as a route for the alteration of metal binding ability is reported. This approach required the development of a direct method for the synthesis of different esters of cysteine from cystine, which then provided access to bicyclic tetramates by Dieckmann cyclisation. Further derivation to ketones and carboxamides by Grignard addition and transamination reactions respectively provided rapid access to a chemical library of tetramates with diverse substitution. Of interest is that bicyclic tetramate ketones and carboxamides showed different tautomeric and metal binding behaviour in solution. Significantly, in both systems, the incorporation of bulky C-5 esters at the bridging position not only reduced metal binding, but also enhanced antibacterial potencies against Gram-positive MRSA bacteria. Those tetramates with antibacterial activity which was not metal dependent showed physiochemical properties of MSA of 559-737 Å2, MW of 427-577 Da, clogP of 1.8-6.1, clogD7.4 of -1.7 to 3.7, PSA of 83-109 Å2 and relative PSA of 12-15% and were generally Lipinski rule compliant. A subset of tetramates exhibited good selectivity towards prokaryotic bacterial cells. Given that the work reported herein is synthesis-led, without the underpinning detailed mechanistic understanding of biological/biochemical mechanism, that the most active compounds occupy a small region of chemical space as defined by MW, clogP, PSA and %PSA is of interest. Overall, the bicyclic tetramate template is a promising structural motif for the development of novel antibacterial drugs, with good anti-MRSA potencies and appropriate drug-like physiochemical properties, coupled with a potential for multi-targeting mechanisms and low eukaryotic cytotoxicity.

Carbene modification and reversible crosslinking of silver nanoparticles for controlled antibacterial activity.

Silver nanoparticles (Ag NPs) system capable of exhibiting different particle size at different temperature was developed, which depended on the extent of Diels-Alder (DA) reaction of bismaleimide with furan. Thus, Ag NPs were functionalized on the surface by a furyl-substituted carbene through an insertion reaction. Subsequent reversible DA crosslinking achieved a controlled aggregation with different particle size, which gives a series of different antibacterial activity. These Ag NPs were characterized by Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), X-ray Photoelectron Spectroscopy (XPS), and Nanoparticle Size Analyzer. The aggregation of the Ag NPs could be reliably adjusted by varying the temperature of DA/reverse-DA reaction. The antibacterial activity was assessed using the inhibition zone method against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), which decreased first and then increased in agreement with the size evolution of Ag NPs. This approach opens a new horizon for the carbene chemistry to modify silver nanoparticles with variable size and give controlled antibacterial activity.

Synthetic Access to Hydrophilic Tetramate Derivatives of Cysteine.

The synthesis, structural, and antibacterial evaluation of bicyclic tetramate derivatives of cysteine rendered hydrophilic with pendant heterocyclic substituents is reported; effective synthetic protocols and antibacterial activity for a small library of polar derivatives were found, and direct evidence for strong metal chelation in these systems was obtained. A computational study has developed a detailed understanding of the controlling factors of the key Dieckmann cyclization step.

Spirocyclic Tetramates by Sequential Knoevenagel and [1,5]-Prototropic Shift.

Highly functionalized spirocyclic tetramates were prepared via a sequential Knoevenagel reaction and [1,5]-prototropic shift (T-reaction) of bicyclic tetramates. While these compounds isomerize in solution, stable analogues can be prepared via an appropriate choice of substituents. Further modification of these compounds allows for the introduction of aromatic groups, making them suitable as skeletons for application in medicinal chemistry.

Synthetic Access to 3-Substituted Pyroglutamic Acids from Tetramate Derivatives of Serine, Threonine, allo-Threonine, and Cysteine.

A general route which provides direct access to pyroglutamates from tetramates, making use of Suzuki coupling on an enol mesylate, followed by reduction, is reported. This work permits direct scaffold hopping from tetramate to substituted pyroglutamates. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria.

Functionalised bicyclic tetramates derived from cysteine as antibacterial agents.

Routes to bicyclic tetramates derived from cysteine permitting ready incorporation of functionality at two different points around the periphery of a heterocyclic skeleton are reported. This has enabled the identification of systems active against Gram-positive bacteria, some of which show gyrase and RNA polymerase inhibitory activity. In particular, tetramates substituted with glycosyl side chains, chosen to impart polarity and aqueous solubility, show high antibacterial activity coupled with modest gyrase/polymerase activity in two cases. An analysis of physicochemical properties indicates that the antibacterially active tetramates generally occupy physicochemical space with MW of 300-600, clog D7.4 of -2.5 to 4 and rel. PSA of 11-22%. This work demonstrates that biologically active 3D libraries are readily available by manipulation of a tetramate skeleton.

Ag NP-Loaded Cotton Fiber Materials: Preparation, Surface Deposition, and Antibacterial Activity with Different Chemical Structures.

An amino-substituted bis(aryldiazomethane) was synthesized and used to modify cotton fibers by a carbene insertion reaction. A subsequent amidation of the modified cotton fibers introduced thioether groups onto the surface. Thus, three different types of cotton fibers with hydroxyl, amine, or thioether groups were expected to bind silver nanoparticles (Ag NPs), which were characterized by scanning electron microscopy to show the surface morphology, as well as X-ray photoelectron spectroscopy, energy-dispersive X-ray spectroscopy, and thermogravimetric analysis to quantify the loading of Ag NPs. A bioassay experiment showed antibacterial activity of the modified cotton fibers. The development of these antibacterial cotton fibers not only gave a clear and deep comparison of different silver-binding approaches but also had potential industrial and daily applications for medical textiles.

Antibacterial Mimics of Natural Products by Side-Chain Functionalization of Bicyclic Tetramic Acids.

Tetramic acids with unsaturated acyl chains are widely found in natural products possessing a range of biological activities, and bicyclic tetramates represent a suitable scaffold to prepare simple mimics of such complex molecules. An efficient route to functionalize the C(6)-acyl group of a bicyclic tetramate was developed and utilized to prepare a small chemical library with a range of saturated and unsaturated side-chains. The analogues with lipophilic residues possessed highly potent antibacterial activity, which was selective for Gram-positive bacteria, and the best compound was 37-fold more potent than the cephalosporin C control and with an appropriate therapeutic window.

Preparation, Post-Modification, and Antibacterial Application of Gelatin Electrospun Membranes.

Two bis(diaryldiazomethane)s substituted with amino groups are synthesized and used for the surface modification of membranes electrospun from gelatin. These membranes are then reacted with tolylene-2,4-diisocyanate to give urea-functionalized materials, so that hydrogen peroxide can be reversibly bound onto their surface. These membranes are characterized by scanning electron microscopy, XPS, differential scanning calorimeter, and tensile test to show their surface properties and bulk properties. The surface modification with amino-substituted diazomethanes and the subsequent cross-linking reaction with diisocyanates contribute to high loadings of hydrogen peroxide, and greatly increase the antibacterial activity of gelatin-derived membranes, which open a new horizon in the preparation of high loading antiseptic/antibacterial biomacromolecular surfaces and interfaces.

Diastereoselective reduction of the tricarbonyl moiety in bicyclic tetramates giving pyroglutamates.

The reduction of C(6)-acyl bicyclic tetramic acids has been achieved with complete diastereoselectivity via catalytic hydrogenation using PtO2. The resulting pyroglutamates had potent antibacterial and anticancer properties and will allow the preparation of simple mimics of pyroglutamate-containing natural products.

Photochromic Materials by Postpolymerisation Surface Modification.

Photochromic materials are available by a postpolymerization surface modification of diverse polymers in a multistep sequential process mediated, first, by carbene insertion chemistry, second, by diazonium coupling with a tethered precursor, and finally by coupling to a spiropyran. This three-step sequence is efficient, and surface loading densities of 1013 molecules cm-2 are typically achievable, leading to materials with observable photochromic and wettability behavior, which operate over multiple cycles without significant photobleaching or loss of efficacy. Materials suitable for application in this process include both reactive, but also lower surface energy polymers. Although the process is particularly efficient for high surface area materials, surface modification onto lower surface area substrates, while being intrinsically less efficient, is nonetheless sufficiently effective that changes in macroscopic photochromic properties are readily observable.