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.

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.

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 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.

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.

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.

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.

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.

Mimics of pramanicin derived from pyroglutamic acid and their antibacterial activity.

Mono and dihydroxypyrrolidinones are readily available by direct oxygenation of a pyroglutamate-derived bicyclic lactam with high diastereoselectivity, and these may be manipulated further in protected or unprotected form by Grignard addition to a pendant Weinreb amide to give acylhydroxypyrrolidinones, which are analogues of the natural product, pramanicin. Preliminary bioassay against S. aureus and E. coli indicated that some compounds exhibit selective Gram-negative antibacterial activity, and may offer promise for the development of novel systems suitable for antibacterial drug development.

Synthesis and bioactivity of fused- and spiro-ß-lactone-lactam systems.

An investigation of the formation of fused- and spiro-ß-lactone annulate to γ-lactams has shown that the fused systems are formed preferentially, under standard conditions, but that spiro systems are accessible only when the formation of the fused system is blocked and require careful optimisation of reaction conditions. These systems display both weak antibacterial activity and proteasome inhibition.

Chemical Space Mimicry for Drug Discovery.

We describe a new library generation method, Machine-based Identification of Molecules Inside Characterized Space (MIMICS), that generates sets of molecules inspired by a text-based input. MIMICS-generated libraries were found to preserve distributions of properties while simultaneously increasing structural diversity. Newly identified MIMICS-generated compounds were found to be bioactive as inhibitors of specific components of the unfolded protein response (UPR) and the VEGFR2 pathway in cell-based assays, thus confirming the applicability of this methodology toward drug design applications. Wider application of MIMICS could facilitate the efficient utilization of chemical space.

Nematicidal Activity of 3-Acyltetramic Acid Analogues Against Pine Wood Nematode, Bursaphelenchus xylophilus.

Among 98 3-acyltetramic acid analogues, compounds 1c, 2c, 2f and 2g, showed >90% nematicidal activity against the pine wood nematode Bursaphelenchus xylophilus at a 10 µg/mL concentration. The nematicidal activities of compounds 1d, 1h, and 2k were a little lower at 88.0%, 85.8%, and 57.2% at a 10 µg/mL concentration, respectively. The nematicidal activity of emamection benzoate, widely used in Korea for the prevention of pine wilt disease, was 32.3% at a 10 µg/mL concentration. Other 3-acyltetramic acid analogues showed less than 30% nematicidal activity. A structure-activity relationship study indicated that the chain length of the C-acyl substituent was very important for high nematicidal activity. All active compounds had C13H27 or C11H23 acyl substituents, in two closely related groups with the common physicochemical properties of a polar surface area 57.6A², PSA (polar surface area) 7.8-8.6% and ClogP (calculated partition coefficient) 5.1-5.9 and a polar surface area 75-84A², PSA 11.1-11.6% and ClogP 4.7-5.1, respectively. Our study indicates that active 3-acyltetramic acid analogues could have potential as lead compounds for developing novel pine wood nematode control agents.

Larvicidal and Nematicidal Activities of 3-Acylbarbituric Acid Analogues against Asian Tiger Mosquito, Aedes albopictus, and Pine Wood Nematode, Bursaphelenchus xylophilus.

Widespread concern for the occurrence of resistant strains, along with the avoidance of the use of highly toxic insecticides and their wide environmental dispersal, highlights the need for the development of new and safer pest control agents. Natural products provide inspiration for new chemical entities with biological activities, and their analogues are good lead compounds for the development of new pest control agents. For this purpose, we evaluated the larvicidal and nematicidal activities of 48 3-acylbarbituric acid analogues against the Asian tiger mosquito, Aedes albopictus and the pine wood nematode, Bursaphelenchus xylophilus, organisms of increasing global concern. Among the 48 3-acylbarbituric acid analogues, four compounds-10, 14d, 14g and 19b-showed >90% larvicidal activity against Ae. albopictus at 10 µg/mL concentration, and one (compound 10) showed the strongest larvicidal activity against Ae. albopictus, with a LC50 value of 0.22 µg/mL. Only compound 18 showed strong nematicidal activity against pine wood nematode. Most active compounds possessed similar physicochemical properties; thus, actives typically had ClogP values of around 1.40-1.50 and rel-PSA values of 16-17% and these similar cheminformatic characteristics reflect their similar structure. This study indicates that active 3-acylbarbituric acids analogues have potential as lead compounds for developing novel mosquito control agents.

New Routes to Functionalize Carbon Black for Polypropylene Nanocomposites.

Methods for chemical surface functionalization for carbon black (CB) nanoparticles were studied to produce (CB)/polypropylene (PP) nanocomposites with superior electrical and thermal properties. Nanoparticle dispersion is known to directly control the extent to which nanocomposites maximize the unique attributes of their nanoscale fillers. As a result, tailored nanoparticle surface chemistry is a widely utilized method to enhance the interfacial interactions between nanoparticles and polymer matrices, assisting improved filler dispersion. In this work, a rapid chemical functionalization approach using a number of diarylcarbene derivatives, followed by the azo-coupling of substituted diazonium salts, for the covalent introduction of selected functional groups to the CB surface, is reported. Characterization of the modified CB by XPS, TGA, CHN, and ATR-IR collectively confirmed surface functionalization, estimating surface grafting densities of the order of 10(13) and 10(14) molecules/cm(2). Nanocomposites, synthesized by solvent mixing PP with pristine and modified CB, demonstrated macroscopic property changes as a result of the nanoparticle surface functionalization. Pronounced improvements were observed for PP nanocomposites prepared with a dodecyl-terminated diaryl functionalized CB, in which TEM analysis established improved nanofiller dispersion owing to the enhanced CB-PP interfacial interactions in the nanocomposite. Observed dielectric relaxation responses at 20 wt % loading and a reduced percolation threshold realized conductivities of 1.19 × 10(-4) S cm(-1) at 10 wt %, compared to 2.62 × 10(-15) S cm(-1) for pristine CB/PP nanocomposites at the same filler loading. In addition, thermal properties signify an increase in the number of nucleation sites by the raised degree of crystallinity as well as increased melting and crystallization temperatures.

Scalar Cross-Relaxation Detected in the NOESY Spectra of Oxazolidines and Thiazolidines.

Anomalous cross-peaks observed in the NOESY spectra of 2,4-disubstituted thiazolidines and oxazolidines that cannot be attributed to classical dipolar NOE or chemical exchange peaks have been investigated experimentally and computationally and have been shown to arise from scalar cross-relaxation of the first kind. This process is stimulated by the relatively slow modulation of scalar couplings and, for the systems studied, arises from slow on-off proton exchange of the amino nitrogen, a process influenced by solution temperature, acidity, and concentration. The mechanism is likely to be significant for many systems in which proton exchange occurs on the millisecond time scale, and misinterpretation of these cross-peaks may lead to erroneous conclusions should their true origins not be recognized.

Chemoselectivity and stereoselectivity of cyclisation pathways leading to bicyclic tetramates controlled by ring-chain tautomerisation in thiazolidines.

Chemoselective Dieckmann cyclisation reactions on N-malonyl thiazolidine templates derived from cysteine and pivaldehyde or aromatic aldehydes may be used to access bicyclic tetramates, for which different pathways operate as a result of differing ring-chain tautomeric behaviour of the respective intermediate imines.

Surface Characterization and in situ Protein Adsorption Studies on Carbene-Modified Polymers.

Polystyrene thin films were functionalized using a facile two-step chemical protocol involving carbene insertion followed by azo-coupling, permitting the introduction of a range of chemical functional groups, including aniline, hexyl, amine, carboxyl, phenyl, phosphonate diester, and ethylene glycol. X-ray photoelectron spectroscopy (XPS) confirmed the success of the two-step chemical modification with a grafting density of at least 1/10th of the typical loading density (10(14)-10(15)) of a self-assembled monolayer (SAM). In situ, real-time quartz crystal microbalance with dissipation (QCM-D) studies show that the dynamics of binding of bovine serum albumin (BSA) are different at each modified surface. Mass, viscoelastic, and kinetic data were analyzed, and compared to cheminformatic descriptors (i.e., c log P, polar surface area) typically used for drug discovery. Results show that functionalities may either resist or adsorb BSA, and uniquely influence its adsorption dynamics. It is concluded that carbene-based surface modification can usefully influence BSA binding dynamics in a manner consistent with, and more robust than, traditional systems based on SAM chemistry.