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Present study involves the synthesis, characterization, antimalarial and anticancer activities of some novel substituted amino analogues of 1,4-naphthoquinone. The chloro group present in the key starting materials like 2,3-dichloro-1,4-naphthoquinone (1) and 2-chloro-3-[trans-4-(4-chlorophenyl)- cyclohexyl]-1,4-naphthoquinone (2) was replaced by substituted amines. These analogues were isolated, purified and screened for antimalarial and anticancer activities. A few of the novel compounds were found to possess substantial biological activity and are reasonably potent.

A novel series of 2/6-aryl/heteroaryl substituted-N-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4-amine analogues have been synthesized from dichloropyrimidines by an initial substitution followed b...

Vaccine discovery and vaccination against preventable diseases are one of most important achievements of the human race. While medical, scientifictechnological advancements have kept in pace and found their way into treatment options for a vast majority of diseases, vaccines as a prevention tool in the public health realm are found languishing in the gap between such innovations and their easy availability/accessibility to vulnerable populations. This paradox has been best highlighted during the unprecedented crisis of the COVID-19 pandemic. As part of a two series publication on the vaccine industry's view on how to accelerate the availability of vaccines worldwide, this paper offers a deep dive into detailed proposals to enable this objective. These first-of-its-kind technical proposals gleaned from challenges and learnings from the COVID-19 pandemic are applicable to vaccines that are already on the market for routine pathogens as well as for production of new(er) vaccines for emerging pathogens with a public health threat potential. The technical proposals offer feasible and sustainable solutions in pivotal areas such as process validation, comparability, stability, post-approval changes, release testing, packaging, genetically modified organisms and variants, which are linked to manufacturing and quality control of vaccines. Ultimately these proposals aim to ease high regulatory complexity and heterogeneity surrounding the manufacturingdistribution of vaccines, by advocating the use of (1) Science and Risk based approaches, (2) global regulatory harmonization, (3) use of reliance, work-sharing, and recognition processes and (4) digitalization. Capitalizingcollaborating on such new-world advancements into the science of vaccines will eventually benefit the world by turning vaccines into vaccination, ensuring the health of everyone.

8, 9, 11-Trichloro-5 H -benzofuro[3,2- c ]carbazol-10-ol analogues have been synthesized by treating 2,3-dihydro-1 H -carbazol-4(9 H )-one with chloranil/fluoranil without any catalyst and is found to be applicable across a range of carbazolone substrates. A possible mechanism has been proposed.

We present a radiation-hardened-by-design (RHBD) memory design that mitigates Single-Event-Transients (SETs), Single-Event-Upsets (SEUs) and Dual-Event-Upsets (DEUs), hence significantly enhancing the reliability of digital signal processors (DSPs) for space applications. We achieve these attributes by combining a Triple-Interlocked Cell (TICE) SRAM cell array and a Triple Modular Redundancy (TMR) voter. The TICE SRAM cells therein self-correct SEUs and DEUs. The TMR voter eliminates SETs. Our proposed RHBD TICE SRAM cells integrated with the TMR voter are also hardened by the layout/sizing RHBD practices. By means of the 128×9-bit memory implementation @ 65nm CMOS, we show that our memory design is inherent SEUand DEU-tolerant, and has 94.83% SET reduction and 92.05% Triple-Event-Upset (TEU) reduction when compared to the memory design embodying the 8-transistor (8-T) SRAM cells. MOE (Min. of Education, S’pore) Accepted version

Metabolic syndrome is a widely prevalent multifactorial disorder associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. High plasma levels of insulin and glucose due to insulin resistance are a major component of the metabolic disorder. Thiazolidinediones (TZDs) are potent PPARγ ligand and used as insulin sensitizers in the treatment of type 2 diabetes mellitus. They are potent insulin-sensitizing agents but due to adverse effects like hepatotoxicity, a safer alternative of TZDs is highly demanded. Here we report synthesis of N-(6-(4-(piperazin-1-yl)phenoxy)pyridin-3-yl)benzenesulfonamide derivatives as an alternate remedy for insulin resistance.

Thiazolidinediones (TZDs) are an important class of compound used for the treatment of type 2 diabetes, targeting the peroxisome proliferator-activated receptor γ (PPARγ). Drug-induced hepatotoxicity, edema, and weight gain are the main concerns associated with TZDs. It was unclear whether the side effects observed are target mediated or compound mediated, but most of the TZDs activate PPARγ. This obliged developing of a new diverse class of ligands as antihyperglycemic agents including non-TZD PPAR ligands that could be highly effective, safe, and devoid of side effects. Here, we report the design and synthesis of N-(5-chloro-6-((1-phenylpiperidin-4-yl)oxy)pyridin-3-yl)benzenesulfonamide derivatives as non-TZD PPARγ modulators.

We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained.

In the last decades many techniques have been proposed to manufacture thin (Several parameters can be adjusted to change the morphology and, hence, the properties of the porous layer, both in the porous silicon formation and the succeeding thermal treatment. This work focuses on the effect of the parameters that control the porous silicon formation on the structure of the porous silicon layer after annealing and, more specifically, on the roughness of the top surface. The reported analysis shows how the roughness of the seed layer can be reduced to improve the quality of the epitaxial growth.

An unknown impurity was detected in the telmisartan bulk drug (active pharmaceutical ingredient – API) using an isocratic reversed-phase high performance liquid chromatography (HPLC). This impurity was isolated by preparative HPLC. Spectral data of the isolated impurity were collected. Based on the spectral data deriving from two dimensional nuclear magnetic spectroscopy (2D-NMR) and mass spectrometry (MS), the impurity was characterized as “methyl 4′,4′-dibromo methyl biphenyl-2-carboxylate”. The arrived structure was further confirmed by theoretical studies.

The thiazolidinediones (TZDs) are a class of oral antidiabetic drugs that improve insulin sensitivity in patients with type 2 diabetes. Although the mechanism by which the TZDs lower insulin resistance is unclear, they are known to target the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor. Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. However, TZDs have several adverse effects, including weight gain and liver toxicity. Herein we report identification of non-TZD PPARγ agonists which exhibit beneficial effects similar to that of TZDs in animal models, but without the associated adverse effects.

In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach.

A simple, economic, and time-efficient stability-indicating, reverse-phase ultra-performance liquid chromatographic (RP-UPLC) method has been developed for analysis of mebeverine hydrochloride in the presence of both impurities and degradation products generated by forced degradation. When mebeverine hydrochloride was subjected to acid hydrolytic, oxidative, base hydrolysis, photolytic, and thermal stress, degradation was observed only in base hydrolysis. The drug was found to be stable to other stress conditions. Successful chromatographic separation of the drug from impurities formed during synthesis and from degradation products formed under stress conditions was achieved on a Waters Acquity C18, 50 mm x 2.1 mm, 1.7 µ particle size column, UV detection at 225 nm and a gradient elution of orthophosphoric acid and acetonitrile as the mobile phase. The method was validated for specificity, precision, linearity, accuracy, and robustness and can be used for quality control during manufacture and for assessm...

Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-α (TNF-α) production is described in the present article. The key reactions involve the formation of a β-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the α,β-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-α production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-α inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-α production in BALB/c mice. Collectively, our findings indicate that these compounds may have potential therapeutic implications for TNF-α-mediated auto-immune/inflammatory disorders.

32nd European Photovoltaic Solar Energy Conference and Exhibition; 1268-1271, Epitaxial silicon foils (

Solid dispersion is molecular dispersion of drug in a polymer matrix which leads to improved solubility and hence better bioavailability. Solvent evaporation technique was employed to prepare films of different combinations of polymers, plasticizer, and a modal drug sulindac to narrow down on a few polymer-plasticizer-sulindac combinations. The sulindac-polymer-plasticizer combination that was stable with good film forming properties was processed by hot melt mixing, a technique close to hot melt extrusion, to predict its behavior in a hot melt extrusion process. Hot melt mixing is not a substitute to hot melt extrusion but is an aid in predicting the formation of molecularly dispersed form of a given set of drug-polymer-plasticizer combination in a hot melt extrusion process. The formulations were characterized by advanced techniques like optical microscopy, differential scanning calorimetry, hot stage microscopy, dynamic vapor sorption, and X-ray diffraction. Subsequently, the best drug-polymer-plasticizer combination obtained by hot melt mixing was subjected to hot melt extrusion process to validate the usefulness of hot melt mixing as a predictive tool in hot melt extrusion process.

Insulin resistance is a characteristic feature of Type 2 diabetes. Insulin resistance has also been implicated in the pathogenesis of cardiovascular disease. Currently used thiazolidinedione (TZD) insulin sensitizers although effective, have adverse side effects of weight gain, fluid retention and heart failure. Using fat cell-based phenotypic drug discovery approach we identified P1736, a novel antidiabetic molecule that has completed Phase II clinical trials. The present study evaluated the in vitro and in vivo pharmacological properties of P1736. P1736 is a non-TZD and it did not activate human PPAR(Peroxisome Proliferator Activated Receptor Gamma )receptors. P1736 caused dose dependent increase in glucose uptake (EC50-400 nM) in the insulin resistant 3T3 adipocytes. The compound (10 µM) induced translocation of GLUT-4 (Glucose Transporter type 4) transporters in these adipocytes while metformin (1.0mM) was inactive. In diabetic db/db mice, P1736 (150 mg/kg) was more efficacious than metformin in lowering plasma glucose (35% vs 25%) and triglyceride levels (38% vs 31%). P1736 tested at 5mg/kg, twice daily doses, reduced glucose by 41% and triglycerides by 32%, in db/db mice. These effects were not associated with adverse effects on body weight or liver function. Rosiglitazone (5mg/kg, twice daily) caused 60% and 40 % decreases in glucose and triglyceride levels, respectively. However, rosiglitazone induced 13% weight gain (p

P276-00 is a novel cyclin-dependent kinase (CDK) inhibitor is in Phase II clinical trials. Valproic acid (VPA), an antiepileptic agent has been associated with anticancer activity, through the inhibition of histone deacetylase I. Here we investigate the effect of the combination of VPA and P276-00, in non-small-cell lung cancer (NSCLC) cell lines.Cell growth inhibition was studied using the Propidium iodide (PI) assay. Cell cycle analysis and recovery were detected by flow cytometry. The expression levels of various proteins were detected by western blot. Inhibition of colony formation in H460 was checked in vitro. In vivo efficacy was studied in H460 xenograft model.The combination of P276-00 and VPA showed synergistic effect on p53+ and p53- NSCLC cell lines in antiproliferative assay at both constant and non-constant ratio with marked decrease in colony forming potential. Flow cytometric analysis confirmed a significant time dependent increase in apoptosis with 64% apoptotic population at 96 h compared to VPA (1%) and P276-00 (28%) alone (p0.0001). Incubation of the cells after treatment, in fresh medium without drugs, led to the recovery of cells treated with P276-00 alone but not the cells treated with the combination of both the drugs. The combination treatment up-regulated tumor suppressor proteins like p53, p21 and p27 along with down-regulation of proliferation and survival proteins viz. cyclin D1 and Bcl-2. This was also associated with the upregulation of the pro-apoptotic protein Bax and significant accumulation of hyperacetylated histones in the combination treatment. Interestingly, VPA in combination with P276-00 was much more effective as an antitumor agent than alone, in the H460 xenograft tumor model in SCID mice.This study indicates that the combination of HDAC inhibitor VPA with CDK inhibitor P276-00 is promising novel molecularly targeted therapeutic approach for NSCLC treatment.

Harmonic analysis is an integral part of system planning, design and operation of power systems. Harmonic voltage and current measurements require synchronized measurements which are complicated and more expensive than ordinary measurements. Generally a large number of measurements are required to estimate the harmonic sources using Harmonic State Estimation techniques. In this work, the harmonic current profile in the power system is estimated using minimal information on the power system structure. A blind signal processing technique using Independent Component Analysis based on basic neural network is applied for the detection of harmonic components generated by nonlinear current loads. The harmonic current estimation is carried out on a five bus system and the results obtained in simulation are transported to the embedded platform .NET Micro framework board.

Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC(50) was obtained in the process. Five most potent compounds with nanomolar IC(50) values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series.

Diacylglycerol acyltransferase, DGAT1, is a promising target enzyme for obesity due to its involvement in the committed step of triglyceride biosynthesis. Amino biphenyl carboxylic acids, exemplified by compound 4, are known potent inhibitors of hDGAT1. However the high cLogP and poor solubility of these biphenyl analogs might tend to limit their development. We have synthesized and evaluated compounds containing 3-phenylisoxazole, 5-phenyloxazole, and 3-phenyl-1,2,4-oxadiazole biaryl units for their hDGAT1 inhibition. Our aim in synthesizing such heterocyclic analogs was to improve the cLogP and solubility of these molecules while retaining hDGAT1 potency. Several compounds within the 3-phenylisoxazole series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Certain promising compounds were studied for their potential to reduce triglyceride levels using an in vivo fat tolerance test in mice and were also evaluated for any possible improvement to their solubility. Compound 40a (IC(50) = 64 nM) with an in vivo plasma triglyceride reduction of 90 percent, and a solubility of 0.43 mg/ml at pH 7.4 may serve as a new lead for developing newer anti-obesity agents.

A key component of the smart grid is the ability to enable dynamic residential pricing to incentivize the customer and the overall community to utilize energy more uniformly. However, the complications involved require that automated strategies be provided to the customer to achieve this goal. This paper presents a solution to the problem of optimally scheduling a set of residential appliances under day-ahead variable peak pricing in order to minimize the customer's energy bill (and also, simultaneously spread out energy usage). We map the problem to a well known problem in computer science - the multiple knapsack problem - which enables cheap and efficient solutions to the scheduling problem. Results show that this method is effective in meeting its goals.

A novel procedure is reported whereby polysubstituted bicyclo[3.3.1] nonane derivatives are prepared in one step from β-ketoesters providing an adequate enolyzing catalyst is used.

Palladium(0) catalysis in the title reaction causes the release of methacrolein which competes effectively with the π-allyl species in product formation, a bicycloannulated derivative, when DBU is used as base.

A 60-year-old lady was admitted in the hospital with the complaints of burning sensation during micturition and abdominal pain. She was diagnosed to have moderate hydronephrosis with left lower 1/3rd ureteric calculus for which ureteroscopy and lithotripsy were done. Her pre-operative random blood sugar was normal. On the 7th postoperative day the patient developed diabetic keto-acidosis which was followed by an acute onset of right sided peri-orbital oedema, proptosis and facial pain. Subsequently she developed diminished vision and lower motor neurone type of Ill, IV and VI cranial nerves paralysis on right side, disorientation and minimal left sided hemiparesis. ENT examination revealed black eschar nasal turbinates, nasal septum and palate and a provisional diagnosis of rhino-orbital cerebral mucormycosis was made. Extensive debridement was done for the patient and the specimen culture showed growth of mucor species. Patient was started on intravenous amphotericin-B and she started improving dramatically. This case of rhino-orbital cerebral mucormycosis with diabetic keto-acidois is presented here for its rarity.

Geetanjali Chimote,1 Jayasree Sreenivasan,1 Nilambari Pawar,1 Jyothi Subramanian,2 Hariharan Sivaramakrishnan,3 Somesh Sharma1,3 1Department of Pharmacology, 2Department of Modeling and Simulation, 3Department of Medicinal Chemistry, Piramal Life Sciences Limited, Mumbai, India Background: Anti-angiogenic therapy in certain cancers has been associated with improved control of tumor growth and metastasis. Development of anti-angiogenic agents has, however, been saddled with higher attrition rate due to suboptimal efficacy, narrow therapeutic windows, or development of organ-specific toxicities. The aim of this study was to evaluate the translational ability of the zebrafish efficacy–toxicity model to stratify anti-angiogenic agents based on efficacy, therapeutic windows, and off-target effects to streamline the compound selection process in anti-angiogenic discovery. Methods: The embryonic model of zebrafish was employed for studying angiogenesis and toxicity. The zebrafish were treated with anti-angiogenic compounds to evaluate their effects on angiogenesis and zebrafish-toxicity parameters. Angiogenesis was measured by scoring the development of subintestinal vessels. Toxicity was evaluated by calculating the median lethal concentration, the lowest observed effect concentration, and gross morphological changes. Results of efficacy and toxicity were used to predict the therapeutic window. Results: In alignment with the clinical outcomes, the zebrafish assays demonstrated that vascular endothelial growth factor receptor (VEGFR) inhibitors are the most potent anti-angiogenic agents, followed by multikinase inhibitors and inhibitors of endothelial cell proliferation. The toxicity assays reported cardiac phenotype in zebrafish treated with VEGFR inhibitors and multikinase inhibitors with VEGFR activity suggestive of cardiotoxic potential of these compounds. Several other pathological features were reported for multikinase inhibitors suggestive of off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy–toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds. Conclusion: The zebrafish efficacy–toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics. Keywords: angiogenesis, therapeutic window, VEGFR inhibitors, zebrafish toxicity assay

Thiazolyl cyclic peptide antibiotics are known for their poor aqueous solubility and unfavorable pharmacokinetics (PK) and hence pose challenging tasks in developing these antibiotics as clinical candidates. In the current paper, we report a possible way to address these challenges with exemplification of our antibiotic PM181104. The approach was to prepare formulations with known excipients, Polysorbate 80 (Tween 80, T-80) and PEG 400 through their varied stiochiometric combination in appropriate ratio to achieve acceptable osmolarity, pH and particle size of the formulation. Two different sets of formulations were prepared with two distinct average particle diameters ranging from 32.8 to 465.4 nm. First, semi-transparent solutions with a particle size of >100 nm were achieved by keeping concentration of PEG 400 constant at 8% (w/v) and decreasing the amounts of T-80. Second, clear colorless solutions with a particle size of, Graphical abstract

A rapid method is proposed for optimization of reliability of multiconstraint parallel redundant systems. The constraints need not be linear. This method provides good starting values, which are close to the boundary of the feasible region, for the number of redundant units in each subsystem. No proof has been presented to establish the optimality obtained by this method. Yet for examples tried out this method provides optimal or near optimal solutions.