Arylazo sulfones: multifaceted photochemical reagents and beyond.

The photochemical action of arylazo sulfones under visible light irradiation has recently gained considerable attention for the construction of carbon-carbon and carbon-heteroatom bonds in organic synthesis. The inherent dyedauxiliary group (-N2SO2R) embedded in the reagent is responsible for the absorption of visible light even in the absence of a photocatalyst, additive or oxidant, leading to the generation of three different radicals, viz. aryl (carbon-centred), sulfonyl (sulphur-centred) and diazenyl (nitrogen-centred) radicals, under different reaction conditions. Encountering a reagent with such a versatile behaviour is quite rare, which makes arylazo sulfones a highly interesting class of compounds. The mild reaction conditions under which these reagents can operate are an added advantage. Recently, they are also being used as non-ionic photoacid generators (PAGs), electron acceptors, and hydrogen atom transfer (HAT) and imination reagents in a number of synthetic transformations. They have displayed substantial damaging effect on the structure of DNA in the presence of light which can lead to their use as phototoxic pharmaceuticals for cancer treatment. Moreover, their photochemistry is also being exploited in polymerization reactions (as photoinitiators) and in materials chemistry (surface modification).

Drug kinetics and antimicrobial properties of quaternary bioactive glasses 81S(81SiO2-(16-x)CaO-2P2O5-1Na2O-xMgO); an in-vitro study.

Bioactive glasses have recently been attracted to meet the challenge in bone tissue regeneration, repair, healing, dental implants, etc. Among the conventional bio-glasses, a novel quaternary mesoporous nano bio-glass with composition 81S(81SiO2-(16-x)CaO-2P2O5-1Na2O-xMgO) (x = 0, 1.6, 2.4, 4 and 8 mol%) employing Stober's method has been explored for examining the above potential application through in-vitro SBF assay, MTT assay, antimicrobial activity and drug loading and release ability. With increasing the MgO concentration up to 4 mol%, from in-vitro SBF assay, we observe that HAp layer develops on the surface of the nBGs confirmed from XRD, FTIR and FESEM. MTT assay using MG-63 cells confirms the biocompatibility of the nBGs having cell viability >225 % for MGO_4 after 72 h which is more than the clinically used 45S5 bio-glass. We have observed cell viability of >125 % even after 168 h. Moreover, MGO_4 is found to restrict the growth of E. coli by 65 % while S. aureus by 75 %, confirming the antimicrobial activity. Despite an increase in the concentration of magnesium, nBGs are found to be non-toxic towards the RBCs up to 4 mol% of MgO while for 8 %, the hemolysis percentage is >6 % which is toxic. Being confirmed MGO_4 nBG as a bioactive material, various concentrations of drug (Dexamethasone (DEX)) loading and release kinetics are examined. We show that 80 % of loading in case of 10 mg-ml-1 and 70 % of cumulative release in 100 h. The mesoporous structure of MGO_4 having an average pore diameter of 5 nm and surface area of 216 m2 g-1 confirmed from BET supports the loading and release kinetics. We conclude that the quaternary MGO_4 nBG may be employed effectively for bone tissue regeneration due to its high biocompatibility, excellent in-vitro cell viability, antimicrobial response and protracted drug release.

In Vivo Cancer Microenvironment Responsive Glycan Receptor-Targeted Nanoparticles for Gemcitabine Delivery to Benzo[a]pyrene-Induced Lung Cancer Model.

Targeted gemcitabine (GEB) loaded 5-N-acetyl-neuraminic acid (Neu5Ac) assembled chitosan nanoparticles (CA-NPs) were formulated by ionotropic gelation process and evaluated for physicochemical and morphological characterization, in vitro and in vivo studies in A-549 cells and lung cancer mice model, respectively. The mean diameter of GEB-CA-Neu5Ac-NPs determined by dynamic light scattering was 161.16 ± 7.70 nm with a polydispersity index (PDI) value of 0.303 ± 0.011 and its zeta potential and entrapment efficiency (%EE) were 40.3 ± 3.45 mv and 66.11 ± 1.94%, respectively. The in vitro cellular uptake studies showed that glycan receptor-targeted nanoparticles deliver significantly more amount (p < 0.001) of GEB into the A-549 lung cancerous cells than non-targeted nanoparticles. The cytotoxicity study using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay clearly demonstrated that GEB-CA-Neu5Ac-NPs have lower IC50 value (6.39 ± 3.78 µg/ml) than others groups that showed that the greater lung cancerous cells inhibition potential of targeted nanoparticles. The in vivo biodistribution of the GEB-loaded 5-N-acetyl-neuraminic acid conjugated chitosan nanoparticles was revealed that targeted nanoparticles showed higher accumulation and retention for an extended period of time due to the active targeting ability of Neu5Ac to glycan receptors. Histopathological examination showed significant recovery in the physiological architecture upon administration of targeted nanoparticles. The glycan receptor-targeted nanoparticles treated groups showed a significant decline in the number of metastatic lung epithelial cells, as compared to the untreated positive control group (p < 0.001) confirming higher anticancer efficacy of the GEB-CA-Neu5Ac-NPs.

pH-influenced self-assembled stealth nanoscaffolds encapsulating memantine for treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurological disorder characterized by the accumulation of ß-amyloid peptides. The only medication used to treat moderate-to-severe AD progression is memantine. In this study, polyethylene glycol (PEG)-coated poly D, L-lactic-co-glycolic acid (PLGA) nanostructures were prepared, as their self-assembling ability helps to penetrate the drug at disease sites with altered pH range (5.7-6.8) due to AD. Drug and polymer interaction studies by FTIR showed no interaction among them, and the thermal properties of drugs, polymers, and nanostructures tell us about their melting behaviour, thermal degradation, and glass transition temperatures. Characterization of prepared self-assembled nanoscaffolds signifies that the acquired properties such as size, structure, surface charges, zeta-potential, stability, thermal properties, biodegradability, biocompatibility, swelling ability, encapsulation, and drug loading provide an efficient therapeutic activity to the nanostructures for the treatment of AD. In addition, parallel artificial membrane permeability assay (PAMPA) has revealed the paracellular transport mechanism of nanoscaffolds across the blood-brain barrier. In vitro release kinetics showed a sustained release pattern exhibiting the Korsmeyer-Peppes drug release kinetic model with a correlation coefficient (R2) value of 0.9905, which describes the drug release pattern from a polymeric system. In vitro enzymatic studies demonstrated the inhibition activity of nanostructures on acetylcholinesterase (AChE), butyrylcholinestrase (BUChE), and ß-secretase enzyme which prevents the breakdown of acetylcholine, butyrylcholine, and amyloid precursor protein, and retention of these neurotransmitters constituted the primary therapeutic strategy for AD. Also, behavioural studies have shown a significant (p<0.05) improvement in cognition behaviour among nanostructures- administered animal groups in a scopolamine-induced amnesia model. The designed nanocarrier can also accelerate the treatment strategies for AD by incorporating stem cells and self-assembled nanoscaffolds that could provide a 3D extracellular matrix to facilitate neuron regeneration, hence improving cognition behaviour effectively.

Dual targeting pH responsive chitosan nanoparticles for enhanced active cellular internalization of gemcitabine in non-small cell lung cancer.

Lung cancer (LC), related with the enhanced expression of epidermal growth factor receptor (EGFR) and sialic acid binding receptors (glycan) brought about the development of EGFR and glycan receptor specific anticancer therapeutics. The current study assessed the formulation, physiochemical characterization, in vitro and in vivo effects of sialic acid (SA) and cetuximab (Cxmab) decorated chitosan nanoparticles (CSN-NPs) loaded with gemcitabine (GMC) targeted to glycan and EGFR over-expressing non-small-cell lung-cancer (NSCLC) A-549 cells. Chitosan (CSN) was conjugated with sialic acid via EDC/NHS chemistry followed by gemcitabine loaded sialic acid conjugated chitosan nanoparticles (GMC-CSN-SA-NPs) were prepared by ionic gelation method decorated with Cxmab by electrostatic interaction. In vitro cytotoxicity of NPs quantified using cell based MTT, DAPI and Annexing-V/PI apoptosis assays showed superior antiproliferative activity of targeted nanoformulations (GMC-CSN-SA-Cxmab-NPs â‰« GMC-CSN-SA-NPs, GMC-CSN-Cxmab-NPs) over non-targeted nanoformulation (GMC-CSN-NPs) against A-549 cells. In vivopharmacokinetic study showed superior bioavailability and in vivo therapeutic efficacy investigation exhibited strongest anticancer activity of glycan and EGFR targeted NPs (GMC-CSN-SA-Cxmab-NPs). GMC-CSN-SA-Cxmab-NPs demonstrated enhanced cellular internalization and better therapeutic potential, by specifically targeting glycan and EGFR on NSCLC A-549 cells and B[a]P induced lung cancer mice model, hence it might be a good substitute for non-targeted, conventional chemotherapy.

'Click' synthesized calcium-chitosan-triazole nanocomplex from CaC2 as an efficient drug carrier, antimicrobial and antioxidant polymer.

A calcium-chitosan-triazole nanocomplex (Ca@CS-Tz) was synthesized via the robust copper catalyzed azide-alkyne cycloaddition using calcium carbide (CaC2) as an in-situ source of acetylene. The nanocomplex was characterized by various techniques and it was proved to be an efficient drug carrier with satisfactory antimicrobial and antioxidant properties. Quercetin loaded nanocomplex (encapsulation efficiency- 68.2 ± 1.0 %) was studied for targeted drug release and the drug release after 120 h was found to be 80.7 ± 0.8 % and 8.69 ± 0.5 % at pH 5.0 and 7.4 respectively. On biological evaluation, the nanocomplex showed enhanced antimicrobial activity against gram-negative bacteria Escherichia coli (E. coli), gram-positive bacteria Bacillus subtilis (B. subtilis) and a fungi Aspergillus niger (A. niger). Moreover, the synthesized Ca@CS-Tz nanocomplex also exhibited significant antioxidant property. Herein, the novel results corresponding to the antimicrobial effect on A. niger and drug delivery studies performed using our previously synthesized chitosan triazole (CS-triazole) derivative have also been reported. Finally, the results of the present study were compared to the results obtained to our previously reported derivative. The incorporation of calcium ions into CS-triazole can lead to the utilization of this complex in various other biomedical applications e.g. bone tissue engineering.

Role of pro-inflammatory cytokines in Alzheimer's disease and neuroprotective effects of pegylated self-assembled nanoscaffolds.

Neurodegeneration and synaptic loss in Alzheimer's disease (AD) lead to impairment in memory functions. Neuroinflammation causes activation of microglia and astrocytes cells that locally and systemically produces inflammatory cytokines which can serve as early diagnostic markers or therapeutic targets in AD. Pro-inflammatory cytokines (Interleukins (IL-1ß, IL-6 and IL-10) and tumor necrosis factor (TNF α)) levels were estimated in serum, cerebral tissue, hepatic tissue, and renal tissue in treatment groups of scopolamine-induced amnesia mice model using ELISA protocol. The results showed that cerebral tissue of AD mice exhibited elevated levels of IL1ß, IL6, IL10 and TNFα which indicate contribution of pro-inflammatory cytokines in the progression of AD. A significant reduction in the concentration of IL1ß, IL-10 and TNF-α were noticed in serum, cerebral tissue and hepatic tissue of animal group treated with marketed memantine tablet (Admenta), pure memantine drug (MEMp), memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds (MEM-PLGA) SANs, Polyethylene Glycol coated memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds [(PEG-MEM-PLGA) SANs] and Polyethylene Glycol coated memantine-poly [(lactic-co-glycolic acid)] self-assembled nanoscaffolds grafted with Bone Marrow Derived Stem Cell ((PEG-MEM-PLGA) SANs-BMSc), whereas a high level of IL-6 was observed in hepatic tissue, cerebral tissue and renal tissues of normal and AD induced mice which showed the emerging potential of IL-6 cytokines that can trigger either neurons survival after injury or causing neurodegeneration and cell apoptosis. The Neuroregenerative potential of stem cells helps in the proliferation of neuronal cell and thus improves cognition in AD animal model.

Adapting Clinical Practice Guidelines for Chronic Kidney Disease: Blood Pressure Management and Kidney Replacement Therapy in Adults and Children in the Saudi Arabian Context Using the Grading of Recommendations Assessment, Development, and Evaluation-ADOLOPMENT Methodology.

This practice guideline was developed by the chronic kidney disease (CKD) Task Force, which was composed of clinical and methodological experts. The Saudi Arabian Ministry of Health and its health holding company commissioned this guideline project to support the realization of Vision 2030's health-care transformation pillar. The synthesis of these guidelines was guided by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)- ADOLOPMENT methodology. The final guidelines addressed 12 clinical questions on the management of blood pressure in patients with CKD through a set of recommen-dations and performance measures. The recom-mendations included antihypertensive agents in children; renin- angiotensin system inhibition (RASi) versus non-RASi in adults; intensive versus standard blood pressure targets; early versus late assessment for kidney replacement therapy (KRT); late versus early preparation strategies for KRT; CKD symptoms during assessment for KRT or conservative manage-ment; initiation of KRT in patients with deteriorating CKD; choice of KRT modality or conservative management in certain CKD patient groups; changing or discontinuing KRT modalities; the frequency of reviews for KRT or conservative management; and information, education, and support. These conditional recommendations were based on a low to very low certainty of evidence, which highlights the need for high-quality randomized trials com-paring different antihypertensive agents in patients with CKD.

Changing paradigms in the treatment of tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis, is a disease long dealt with, but still remains the second leading cause of death world-wide. The current anti-tubercular chemotherapy primarily targets the microbial pathogenesis, which however, is failing due to the development of drug resistance. Moreover, with fewer new drugs reaching the market, there is a need to focus on alternate treatment approaches that could be used as stand-alone or adjunct therapy and the existing drugs, referred to as Track II chemotherapy. This article is an attempt to review the changing global patterns of tuberculosis and its treatment. Further, newer drug delivery approaches like multi-particulate drug carriers which increase the therapeutic efficacy and bring down the systemic toxicity associated with drugs have also been discussed. There is also a need to use interventions which can be used as Track II therapy. Host-directed therapeutics (HDT) is an emerging area concept in which host cell functions and hence the response to pathogens can be modulated, which can help manage TB. HDT decreases damage induced due to inflammation and necrosis in the lungs and other parts of the body due to the disease. Various immuno-modulatory pathways have been discussed in this review which could be explored further to treat TB. An in-depth understanding of multi-particulate drug carriers and HDT could help in dealing with tuberculosis; however, there is still a long way to go.

Design, fabrication, optimization and characterization of memantine-loaded biodegradable PLGA nanoscaffolds for treatment of Alzheimer's disease.

This study aimed to design and develop nanoscaffolds for the controlled release of memantine by non-solvent-induced phase separation (N-TIPS) method. The development and optimization of nanoscaffolds was performed by Box-Behnken Design in which two independent formulation variables and one independent process variable: poly(lactic-co-glycolic acid) (PLGA) (X1), Pluronics F-127 (X2), and rotation speed (X3) were used. The design provided 15 formulation designs which were prepared to determine the response: percentage porosity (Y1) and drug loading (Y2). Polynomial equations were generated and analyzed statistically to establish a relationship between independent and dependent variables and develop an optimal formulation with maximized porosity (%) and drug loading (%). The optimized formulation batch was prepared using 19.18% w/v PLGA, 4.98% w/v Pluronics at 500 rpm rotation speed and exhibited drug loading of 11.66% and porosity of 82.62%. Further, correlation between the independent and dependent variables were established and statistically analyzed by using model generated mathematical regression equations, ANOVA, residual plots, interaction plot, main effect plot, contour plot and response surface designs. The analysis of model showed the significant individual effect of PLGA and significant interactive effect of Pluronics F-127 and rotation speed on drug loading and porosity. Further, its physicochemical characterization, andin-vitro(drug release kinetics, and PAMPA study),ex-vivo(enzyme inhibition assay and pro-inflammatory cytokines study) andin-vivo(neurobehavioral and histological study) studies were performed to evaluate the potential of memantine-loaded nanoscaffolds in the treatment of Alzheimer's disease (AD).

New paradigm in combination therapy of siRNA with chemotherapeutic drugs for effective cancer therapy.

Chemotherapeutics drugs play a pivotal role in the treatment of cancer. However, many issues generate by chemotherapy drugs, including unfavorable harm to healthy cells and multidrug resistance (MDR), persist and have a negative impact on therapeutic outcomes. When compared to monotherapy, combination cancer therapy has many advantages, like improving efficacy through synergistic effects and overcoming drug resistance. Combination treatment may comprise several chemotherapeutics drugs and combinations of chemotherapeutic drugs with some other therapeutic options such as surgery or radiation. Cancer treatment that utilizes co-delivery strategies with siRNA and chemotherapeutic drugs has been shown to have highly effective antitumor effects in the treatment of many cancers. However, the highly complex mechanisms of chemotherapeutic drugs-siRNA pairs during the co-delivery process have received little attention. The ideal combination of chemotherapeutic drugs with siRNA is very crucial for producing the desirable anticancer effects that would greatly enhance therapeutic efficiency. This review puts an emphasis on the logic for choosing suitable chemotherapeutic drug-siRNA combinations, which may open the way for the co-delivery of chemotherapeutic drugs and siRNA for treating cancer in the clinic. This review summarizes recent breakthrough in the area of diverse mechanism-based chemotherapeutic drugs-siRNA combinations in cancer treatment.

A photocatalyst-free visible-light-mediated solvent-switchable route to stilbenes/vinyl sulfones from ß-nitrostyrenes and arylazo sulfones.

Photocatalyst-free visible-light-mediated reactions, based on the presence of a visible-light-absorbing functional group in the starting material itself in order to exclude the often costly, hazardous, degradable and difficult to remove or recover photoredox catalysts, have been gaining momentum recently. We have employed this approach to develop a denitrative photocatalyst-free visible-light-mediated protocol for the arylation/sulfonylation of ß-nitrostyrenes employing arylazo sulfones (bench-stable photolabile compounds) in a switchable solvent-controlled manner. Arylazo sulfones served as the aryl and sulfonyl radical precursors under blue LED irradiation for the synthesis of trans-stilbenes and (E)-vinyl sulfones in CH3CN and dioxane/H2O 2 : 1, respectively. The absence of any metal, photocatalyst and additive; excellent selectivity (E-stereochemistry) and solvent-switchability; and the use of visible light and ambient temperature are the prime assets of the developed method. Moreover, we report the first photocatalyst-free visible light-driven route to synthesize stilbenes and vinyl sulfones from readily available ß-nitrostyrenes.

Organic photoredox catalysis enabled cross-coupling of arenediazonium and sulfinate salts: synthesis of (un)symmetrical diaryl/alkyl aryl sulfones.

We disclose herein the first transition-metal- and external oxidant/reductant-free visible-light-mediated synthesis of (un)symmetrical diaryl/alkyl aryl sulfones from arenediazonium tetrafluoroborates and sodium sulfinates using eosin Y as an organic photoredox catalyst. The utilization of visible light as an inexpensive and ecosustainable energy source, operational simplicity, ambient temperature and clean reaction in aqueous acetonitrile are the salient features of the developed protocol. The desired sulfones were also synthesized via a one-pot, two-step process directly from anilines and sulfinate salts in good to excellent yields.

Polylactide-co-glycolide nanoparticles of antitubercular drugs: formulation, characterization and biodistribution studies.

BACKGROUND: The present study was designed to prepare and characterize poly lactide-co-glycolide nanoparticles of antitubercular drugs (ATDs) for delivery through oral route to alveolar macrophages. METHODS: Nanoparticles were prepared by double emulsification solvent evaporation method. Ex vivo and in vivo drug accumulation studies were performed in alveolar macrophages, harvested by broncheoalveolar lavaging. Internalization of nanoparticles was studied by confocal laser scanning microscopy. γ-scintigraphy imaging using technetium-99m was done to study the biodistribution pattern of nanoparticles. RESULTS: High intracellular concentrations of ATDs were observed in macrophages within 30 min of administration of nanoparticles. Intense radioactivity recorded in liver, spleen and lungs revealed uptake of nanoparticles in macrophages, abundantly present in mononuclear phagocyte system present in these organs. CONCLUSION: Targeted delivery of ATDs will help reduce dose and associated side effects including hepatotoxicity of ATDs. Further studies are required to assess the potential therapeutic advantages for treatment of TB.

Aerobic oxysulfonylation of alkenes using thiophenols: an efficient one-pot route to ß-ketosulfones.

We have developed a highly efficient synthetic route to ß-ketosulfones via AgNO3 catalyzed oxysulfonylation of alkenes using thiophenols in the presence of air (O2) and K2S2O8 as eco-friendly oxidants. Thiophenols have been used as sulfonylation precursors for the first time in a dioxygen activation based radical process. Moreover, the protocol also offers a new and convenient method for the synthesis of ß-hydroxysulfides at room temperature without the use of any initiator.

Development and optimization of polymeric nanoparticles of antitubercular drugs using central composite factorial design.

OBJECTIVE: The objective of the present study was to develop sustained release biodegradable polymeric nanoparticles (PNs) of two anti-tubercular drugs (ATDs), rifampicin (RIF) and isoniazid (INH) using circumscribed central composite factorial design (CCD) and evaluate in vivo uptake potential using rhodamine labeled PNs (RPNs). METHODS: CCD was employed to study the influence of independent formulation factors, drug:polymer ratio (D:P) and surfactant concentration (SC), on dependent physicochemical characteristics, particle size (PS), polydispersity index (PI) and percentage entrapment efficiency (%EE) of the drugs. Optimized PNs prepared using response surface methodology (RSM) were evaluated for in vitro kinetics at endosomal macrophage pH 5.2 and physiological pH 7.4 and in vivo targeting potential in peritoneal macrophages (PMs) by fluorescence microscopy (FM) and confocal laser scanning microscopy (CLSM). RESULTS: Optimized PNs exhibited spherical and porous surface with a mean PS of 202 nm, PI of 0.178, zeta potential of -25.49 mV and %EE of 76.12% and 54.25% for RIF and INH, respectively. CONCLUSIONS: Highly hydrophilic INH could be encapsulated with lypophilic RIF with efficiency. In vivo uptake studies of RPNs in PMs suggested endocytosis of RPNs without any surface adsorption phenomenon. Hence, further studies need to be performed for establishing the pharmacokinetic potential of PNs.

Intranasal curcumin and its evaluation in murine model of asthma.

Curcumin, a phytochemical present in turmeric, rhizome of Curcuma longa, has been shown to have a wide variety of pharmacological activities including anti-inflammatory, anti-allergic and anti-asthmatic properties. Curcumin is known for its low systemic bioavailability and rapid metabolization through oral route and has limited its applications. Over the recent decades, the interest in intranasal delivery as a non-invasive route for drugs has increased as target tissue for drug delivery since nasal mucosa offers numerous benefits. In this study, we evaluated intranasal curcumin following its absorption through nasal mucosa by a sensitive and validated high-performance liquid chromatography (HPLC) method for the determination of intranasal curcumin in mouse blood plasma and lung tissue. Intranasal curcumin has been detected in plasma after 15 min to 3 h at pharmacological dose (5 mg/kg, i.n.), which has shown anti-asthmatic potential by inhibiting bronchoconstriction and inflammatory cell recruitment to the lungs. At considerably lower doses has proved better than standard drug disodium cromoglycate (DSCG 50 mg/kg, i.p.) by affecting inflammatory cell infiltration and histamine release in mouse model of asthma. HPLC detection revealed that curcumin absorption in lungs has started after 30 min following intranasal administration and retained till 3h then declines. Present investigations suggest that intranasal curcumin (5.0 mg/kg, i.n.) has effectively being absorbed and detected in plasma and lungs both and suppressed airway inflammations at lower doses than the earlier doses used for detection (100-200 mg/kg, i.p.) for pharmacological studies (10-20 mg/kg, i.p.) in mouse model of asthma. Present study may prove the possibility of curcumin as complementary medication in the development of nasal drops to prevent airway inflammations and bronchoconstrictions in asthma without any side effect.

NHC-catalysed diastereoselective synthesis of multifunctionalised piperidines via cascade reaction of enals with azalactones.

NHC-catalysed azalactone ring-opening and piperidine ring-closing cascade with α,ß-unsaturated aldehydes (enals) in a one-pot operation is reported. The present reaction cascade offers a convenient method for a highly diastereoselective synthesis of multifunctionalised piperidines in excellent yields under mild conditions.