Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4-dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.     

Algorithms for non-uniform size data placement on parallel disks

We study an optimization problem that arises in the context of data placement in a multimedia storage system. We are given a collection of M multimedia objects (data items) that need to be assigned to a storage system consisting of N disks d₁,d₂,…,d_N. We are also given sets U₁,U₂,…,U_M such that U_i is the set of clients seeking the ith data item. Data item i has size s_i. Each disk d_j is characterized by two parameters, namely, its storage capacity C_j which indicates the maximum total size of data items that may be assigned to it, and a load capacity L_j which indicates the maximum number of clients that it can serve. The goal is to find a placement of data items to disks and an assignment of clients to disks so as to maximize the total number of clients served, subject to the capacity constraints of the storage system.We study this data placement problem for homogeneous storage systems where all the disks are identical. We assume that all disks have a storage capacity of k and a load capacity of L. Previous work on this problem has assumed that all data items have unit size, in other words s_i=1 for all i. Even for this case, the problem is NP-hard. For the case where s_i{1,…,Δ} for some constant Δ, we develop a polynomial time approximation scheme (PTAS). This result is obtained by developing two algorithms, one that works for constant k and one that works for arbitrary k. The algorithm for arbitrary k guarantees that a solution where at least -fraction of all clients are assigned to a disk (under certain assumptions). In addition we develop an algorithm for which we can prove tight bounds when s_i{1,2}. In fact, we can show that a -fraction of all clients can be assigned (under certain natural assumptions), regardless of the input distribution.     

Manufacturer cooperation in supplier development under risk

Supplier development involves efforts undertaken by manufacturing firms to improve their suppliers’ capabilities and performance. These improvement efforts can be targeted at a variety of areas such as quality management, product development, and cost reduction. Since supplier development requires investments on the part of the manufacturer, it is important to optimally allocate investment dollars among multiple suppliers to minimize risk while maintaining an acceptable level of return. This paper presents a set of optimization models that address this issue. We consider two scenarios: single-manufacturer and multiple suppliers (SMMS) and two-manufacturer and multiple suppliers (TMMS). In the SMMS case, we suggest optimal investments in various suppliers by effectively considering risk and return. The TMMS case investigates whether manufacturers with differing capabilities could gain risk reduction benefits from cooperating with each other in supplier development. Through illustrative applications, we identify conditions in which both cooperation and non-cooperation are beneficial for manufacturers. Under conditions of cooperation, we propose optimal investments for manufacturers to achieve high levels of risk reduction benefits.     

From subtle to substantial: role of metal ions on pi-pi interactions

Quantum chemistry calculations reveal that the subtle pi-pi interactions, usually in the range 2-4 kcal/mol, will become substantially significant, from 6 to 17 kcal/mol, in the presence of metal ion. The metal ions have higher affinity toward a pi-pi dimer compared to a single pi-moiety. Considering the widespread occurrence of cation-pi-pi motifs in chemistry and biology, as evident from the database analysis, we propose that the two key noncovalent forces, which govern the macromolecular structure, cation-pi and pi-pi, work in concert.     

WEB‐spline based mesh‐free finite element analysis for the heat equation and the time‐dependent Navier–Stokes equation: A survey

In this article, we give some numerical techniques and error estimates using web‐spline based mesh‐free finite element method for the heat equation and the time‐dependent Navier–Stokes equations on bounded domains. The web‐spline method uses weighted extended B‐splines on a regular grid as basis functions and does not require any grid generation. We demonstrate the method by providing numerical results for the Poisson's and stationary Stokes equation. © 2012 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq, 2013     

New quinoxaline-piperazine-oxazole conjugates: Synthesis,in vitro anticancer,in silico ADMET,and molecular docking studies

In this paper, we describe the synthesis of some new quinoxaline-piperazine-oxazole amide conjugates 6a-n from 3-chloroquinoxaline-2-carbonitrile using well-known reaction sequences. The synthesized compounds were characterized by ¹H NMR,¹³C NMR, and mass spectral analysis. The compounds were tested for their in vitro antiproliferative activity toward four different cancer cell lines such as PC-3, MCF-7, DU-145, and A-549 by MTT method. The compounds, 6c, 6h, 6i , and 6n were found to be more potent than the standard Erlotinib. In vitro tyrosine kinase EGFR inhibition studies using four potent compounds revealed that 6n has double inhibiting tendency with value IC₅₀ of 0.22 μM and 6h with value of IC₅₀ 0.27 μM compared to reference compound. Molecular docking studies of active compounds, 6c , 6h , 6i , and 6n on EGFR receptor suggested that all the compounds have more binding energies than that of Erlotinib. Furthermore, the in silico pharmacokinetic profile was accomplished for the active compounds, 6c , 6h , 6i , and 6n using SWISS/ADME and pk CSM, whereas compounds, 6h , 6i , and 6c followed Lipinski rule, Veber rule, Egan rule and Muegge rule. The remaining compound 6n did not follow Lipinski rule, Ghose rule because one common violation, that is, because of high molecular weight (MW > 350).     

Synthesis and antiviral activity of novel imidazo[2,1-b]thiazoles coupled with morpholine and thiomorpholines

Herein described the synthesis and antiviral evaluation of a novel series of morpholine and thio-morpholine coupled imidazo[2,1-b]thiazoles. The three-step reaction sequence involving the condensation of 1,3-dichloroacetone with thiourea followed by coupling with morpholine and thiomorpholine and finally cyclization with substituted α-bromoacetophenones yielded the desired imidazothiazoles 7(a–l) . Screening of all the new compounds for their in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells, resulted in two potent analogs, 7d (IC₅₀: 1.1 μM, C₅₀: >300 μM, SI = 273) and 7e (IC₅₀: 2.0 μM, C₅₀: >300 μM, SI = 150), with a favorable toxicity profile and are the best anti-influenza hit analogs for further structural optimization.     

A New Class of Stabilized WEB-Spline-Based Mesh-Free Finite Elements for the Approximation of Maxwell Equations

The objective of this article is to discuss the existence and the uniqueness of a weighted extended B-spline-(WEB-spline) based discrete solution for the Maxwell equations in low frequency limit. The domain is composed of insulating and conducting regions. This problem has saddle point structure where the electric field in insulating region is the Lagrange multiplier that forces curl-free constraint on the magnetic field.     

Tritium in water bodies around the Kaiga generating station

Tritium concentration was monitored in different water sources collected around Kaiga Nuclear Power plant, India. The concentration was in the ranges?<?1.9–27.4 Bq L^?1 (GM?=?4.0 Bq L^?1) for groundwater,?<?1.9–42.1 Bq L^?1 (GM?=?3.5 Bq L^?1) for surface water and in 12.4–42.0 Bq L^?1 (GM?=?24.07 Bq L^?1) for reservoir water. The concentration values observed in this study are similar to those reported for other PHWR stations of the world. The radiation dose to the public due to ingestion of Tritium through groundwater was computed to be 0.08 μSvy^?1.

     

Design,Synthesis, and Biological Evaluation of 1,2,4-Oxadiazole-Isoxazole Linked Quinazoline Derivatives as Anticancer Agents

Russian Journal of General Chemistry - A series of novel 1,2,4-oxadiazole-isoxazole linked quinazoline compounds is designed, synthesized and screened for anticancer activity on four human cancer...