Synthesis and Evaluation of c-Src Kinase Inhibitory Activity of Pyridin-2(1H)-one Derivatives

Src kinase, a prototype member of the Src family of kinases (SFKs), is over-expressed in various human tumors, and has become a target for anticancer drug design. In this perspective, a series of eighteen 2-pyridone derivatives were synthesized and evaluated for their c-Src kinase inhibitory activity. Among them, eight compounds exhibited c-Src kinase inhibitory activity with IC50 value of less than 25 μM. Compound 1-[2-(dimethylamino)ethyl]-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-one (36) exhibited the highest c-Src kinase inhibition with an IC50 value of 12.5 μM. Further the kinase inhibitory potential of compound 36 was studied for EGFR, MAPK and PDK, however no significant activity was observed at the highest tested concentration (300 μM). These results provide insights for further optimization of this scaffold for designing the next generation of 2-pyridone derivatives as candidate Src kinase inhibitors

BUCCAL ADHES IVE DRUG DELIVERY S YSTEM: SAFER DELIVERY OF BIOTHERAPEUTICS

The route of administration is critical for any medicine. For decades, the most common dosage forms were either oral or injection. Patients generally preferred oral therapies over injected medications because oral delivery is non-invasive and convenient. Drug delivery by buccal route presents unique advantages that are not available with other modes of administration. Buccal drug delivery is a promising option where common drug administrations (e.g., intravenous, intramuscular) are inapplicable. Recently, it has been shown that many drugs have better bioavailability by buccal route than by oral route. This has been attributed to rich vasculature and a highly permeable structure of the buccal mucosa coupled with avoidance of hepatic first-pass elimination, gut wall metabolism and/or destruction in the gastrointestinal tract. The physiology of the buccal mucosa offers a promising route for non-invasive systemic delivery of biotherapeutics. The present article highlights the advantages, physicochemical factors and formulation related parameters affecting the buccal drug delivery. It also includes a note on polymer used in buccal drug delivery and buccal drug absorption pathways. Key Words: Buccal route, bioavailability, non-invasive, Biotherapeutic

Characterization of maize genotypes using microsatellite markers associated with QTLs for kernel iron and zinc

224-234Crop genetic resources rich in Fe and Zn provide sustainable and cost-effective solution to alleviate micronutrient malnutrition. Maize being the leading staple crop assumes great significance as a target crop for biofortification. We report here wide genetic variation for kernel Fe and Zn among 20 diverse maize inbreds lines, majority of which were bred for quality protein maize (QPM) and provitamin-A. Kernel Fe ranged from 30.0 - 46.13 mg/kg, while kernel Zn ranged from 8.68-39.56 mg/kg. Moderate but positive correlation was observed between the micronutrients. Characterization using 25 Single sequence repeats (SSRs) linked to QTLs for kernel Fe produced 58 alleles. Similarly, 86 alleles were identified from 35 SSRs linked to QTLs for kernel Zn. One unique allele for kernel Fe and three unique alleles for kernel Zn were identified. The mean polymorphic information content (PIC) was 0.40 for both kernel Fe and  Zn. Jaccard’s dissimilarity coefficients varied from 0.25 - 0.91 with a mean of 0.58 for kernel-Fe while 0.27- 0.88 with a mean of 0.57 for kernel Zn. Principal coordinate analysis depicted diversity of inbreds. Cluster analysis grouped the inbreds into three major clusters for both kernel Fe and Zn. Potential cross combinations have been proposed to develop micronutrient rich hybrids and novel inbreds with higher Fe and Zn. The information generated here would help the maize biofortification programme to develop nutritionally enriched hybrids

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Synthesis and antibacterial activity screening of <em>N</em>- and <em>O</em>-substituted quinolin-2-one acetamide derivatives

1243-1250A series of new quinolin-2-one acetamide derivatives have been synthesized and characterized; their antibacterial potential investigated, against three Gram-positive pathogenic strains namely Bacillus cereus, Bacillus subtilis and Staphylococcus aureus and four Gram-negative pathogenic strains namely Pseudomonas aeruginosa, Escherichia coli, Salmonella typhimurium and Klebsiella pneumoniae by disc diffusion assay at a concentration of 250 μg/disc. Two of these compounds, which are O-substituted quinolin-2-one acetamides exhibit moderate activity against six bacterial strains B. cereus, B. subtilis, S. aureus, P. aeruginosa, E. coli and S. typhimurium

<span style="font-size:15.0pt;mso-bidi-font-size: 14.0pt;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman";text-transform:uppercase;letter-spacing: -.1pt;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language: AR-SA" lang="EN-US">S<span style="font-size:15.0pt;mso-bidi-font-size: 14.0pt;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman";letter-spacing:-.1pt;mso-ansi-language: EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA" lang="EN-US">ynthesis and characterization of new <i style="mso-bidi-font-style:normal">N</i>-alkylated pyridin-2(1<i style="mso-bidi-font-style:normal">H</i>)-ones</span></span>

492-500A series of novel N-substituted pyridin-2(1H)-one derivatives have been synthesized by reacting (E)-ethyl 3-(6-fluoro-4-oxo-4H-chromen-3-yl)acrylate, with various alkylamines, benzylamines, diaminoalkanes, propargyl amine, 2-amino-1,3-dihydroxypropane, etc. under basic conditions, in 60-83% yield. The structures of the compounds have been established on the basis of their physical and spectral characterization data (1H and 13C NMR, UV-Vis, FT-IR, and HRMS) and further confirmed by X-ray crystallographic analysis of a representative compound. Antibacterial activity of obtained 2-pyridones have been investigated against three human pathogen bacterial strains. Most of the compounds exhibit low activity as compared to the reference

Structure and magnetic properties of Ti1−xCoxO2 nanoparticles prepared by chemical route

The structural, microstructural, dielectric and ferromagnetic behavior of Co-doped TiO2 (TC) nanoparticles have been studied. TC nanoparticles were prepared by a chemical synthesis route using polyethylene glycol as a surfactant. The polymer serves as a surfactant to encapsulate the cationic species in divided groups during the reaction that confines the size and morphology of the specimen. X-ray diffraction pattern has been used to confirm the crystalline structure (rutile or anatase) and average particle size is measured using Debye–Scherer's relation. The particle's size is also measured by transmission electron microscopy. Fourier transform infrared spectroscopy has been used to confirm the formation of Ti–O bond. X-ray photoemission spectroscopy suggests that the Ti and Co ions have the oxidation states 4+ and 2+, respectively, present in the 2p region and confirm the presence of Ti–O–Co bonds. The variation in magnetization with Co concentration is studied. Dielectric measurements were also carried at room temperature to confirm the storage charge capability of TC semiconductor, and the nano-size effect to control the dielectric constant up to higher frequency region has been observed. The enhancement in magnetization at room temperature is also observed

Dynamics of forest malaria transmission in Balaghat district, Madhya Pradesh, India.

BACKGROUND: An epidemiological and entomological study was carried out in Balaghat district, Madhya Pradesh, India to understand the dynamics of forest malaria transmission in a difficult and hard to reach area where indoor residual spray and insecticide treated nets were used for vector control. METHODS: This community based cross-sectional study was undertaken from January 2010 to December 2012 in Baihar and Birsa Community Health Centres of district Balaghat for screening malaria cases. Entomological surveillance included indoor resting collections, pyrethrum spray catches and light trap catches. Anophelines were assayed by ELISA for detection of Plasmodium circumsporozoite protein. FINDINGS: Plasmodium falciparum infection accounted for >80% of all infections. P. vivax 16.5%, P. malariae 0.75% and remaining were mixed infections of P. falciparum, P. vivax and P. malariae. More than, 30% infections were found in infants under 6 months of age. Overall, an increasing trend in malaria positivity was observed from 2010 to 2012 (chi-square for trend  =  663.55; P<0.0001). Twenty five Anopheles culicifacies (sibling species C, D and E) were positive for circumsporozoite protein of P. falciparum (44%) and P. vivax (56%). Additionally, 2 An. fluviatilis, were found positive for P. falciparum and 1 for P. vivax (sibling species S and T). An. fluviatilis sibling species T was found as vector in forest villages for the first time in India. CONCLUSION: These results showed that the study villages are experiencing almost perennial malaria transmission inspite of indoor residual spray and insecticide treated nets. Therefore, there is a need for new indoor residual insecticides which has longer residual life or complete coverage of population with long lasting insecticide treated nets or both indoor residual spray and long lasting bed nets for effective vector control. There is a need to undertake a well designed case control study to evaluate the efficacy of these interventions