Synthesis and antitubercular activity of substituted novel pyrazoline derivatives

A series of 2-2-methoxy-4-[5-(substituted phenyl)1-(4-pyridylcarbonyl)-4,5-dihydro-1H-3-pyrazolyl] phenoxyacetic acid were synthesized by the reaction between isoniazid (INH) and chalcones, and were tested for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv and INH resistant M. tuberculosis using BACTEC-460 radiometric system and agar dilution method. Among the synthesized compounds, Compounds II 2-4-[5-(4-hydroxyphenyl)-1-(4-pyridylcarbonyl)-4,5-ihydro-1H-3-pyrazolyl]-2-methoxy phenoxy acetic acid was found to be most active agent against M. tuberculosis H37Rv (MTB) and INH resistant M. tuberculosis (INHR-MTB), with minimum inhibitory concentration of 0.12 microM, when compared to INH 5.6-fold more active against MTB and 78-fold more active against INHR-MTB, respectively.     

In vitro discriminative antipseudomonal properties resulting from acyl substitution of N-terminal sequence of dermaseptin s4 derivatives

Truncation and acylation were combined to investigate the broad-spectrum bactericidal and hemolytic peptide S4(1-15). Substitution of up to seven residues with dodecanoic acid (C(12)) gradually led to specific antipseudomonal activity: out of 40 bacterial strains tested in vitro, C(12)-S4(8-15) displayed similar minimal inhibitory concentrations (MICs) as S4(1-15) against Pseudomonas aeruginosa sp. (identical MIC(90)) but was practically inactive against most other bacteria or erythrocytes. Surface plasmon resonance and isothermal titration calorimetry experiments revealed the binding properties of S4(1-15) to be consistent with its nonselective activities, while discriminative activities of C(12)-S4(8-15) correlated with high binding affinity to a membrane containing pseudomonal lipopolysaccharides and with lower affinities to membranes containing nonpseudomonal lipopolysaccharides or cholesterol. Various mechanistic studies failed to detect significant differences in secondary structure, bactericidal kinetics, or ability to perturb the cytoplasmic membrane, pointing to a similar mode of action.     

Complexity measures of sign matrices

In this paper we consider four previously known parameters of sign matrices from a complexity-theoretic perspective. The main technical contributions are tight (or nearly tight) inequalities that we establish among these parameters. Several new open problems are raised as well. Supported by the ISF. Supported by the ARC.     

Effect of backbone flexibility on charge transfer rates in peptide nucleic acid duplexes

Charge transfer (CT) properties are compared between peptide nucleic acid structures with an aminoethylglycine backbone (aeg-PNA) and those with a γ-methylated backbone (γ-PNA). The common aeg-PNA is an achiral molecule with a flexible structure, whereas γ-PNA is a chiral molecule with a significantly more rigid structure than aeg-PNA. Electrochemical measurements show that the CT rate constant through an aeg-PNA bridging unit is twice the CT rate constant through a γ-PNA bridging unit. Theoretical calculations of PNA electronic properties, which are based on a molecular dynamics structural ensemble, reveal that the difference in the CT rate constant results from the difference in the extent of backbone fluctuations of aeg- and γ-PNA. In particular, fluctuations of the backbone affect the local electric field that broadens the energy levels of the PNA nucleobases. The greater flexibility of the aeg-PNA gives rise to more broadening, and a more frequent appearance of high-CT rate conformations than in γ-PNA.     

Return of the quantum cosmic censor

The influential theorems of Hawking and Penrose demonstrate that spacetime singularities are ubiquitous features of general relativity, Einstein's theory of gravity. The utility of classical general relativity in describing gravitational phenomena is maintained by the cosmic censorship principle. This conjecture, whose validity is still one of the most important open questions in general relativity, asserts that the undesirable spacetime singularities are always hidden inside of black holes. In this Letter we reanalyze extreme situations which have been considered as counterexamples to the cosmic censorship hypothesis. In particular, we consider the absorption of fermion particles by a spinning black hole. Ignoring quantum effects may lead one to conclude that an incident fermion wave may over spin the black hole, thereby exposing its inner singularity to distant observers. However, we show that when quantum effects are properly taken into account, the integrity of the black-hole event horizon is irrefutable. This observation suggests that the cosmic censorship principle is intrinsically a quantum phenomena.     

On closures of orbits and arithmetic of quaternions

ForG=PGL₂(ℚ _p )×PGL₂ ℚ we study the closures of orbits under the maximal split Cartan subgroup ofG in homogeneous spacesΓ\G. We show that if a closure of an orbit contains a closed orbit then the orbit is either dense or closed. We show the relation of this to divisibility properties of integral quaternions and other lattices. Sponsored in part by the Edmund Landau Center for Research in Mathematical Analysis supported by the Minerva Foundation (Germany). Research at MSRI supported by NSF grant DMS8505550.     

PNA versus DNA: effects of structural fluctuations on electronic structure and hole-transport mechanisms

The effects of structural fluctuations on charge transfer in double-stranded DNA and peptide nucleic acid (PNA) are investigated. A palindromic sequence with two guanine bases that play the roles of hole donor and acceptor, separated by a bridge of two adenine bases, was analyzed using combined molecular dynamics (MD) and quantum-chemical methods. Surprisingly, electronic structure calculations on individual MD snapshots show significant frontier orbital electronic population on the bridge in approximately 10% of the structures. Electron-density delocalization to the bridge is found to be gated by fluctuations of the covalent conjugated bond structure of the aromatic rings of the nucleic bases. It is concluded, therefore, that both thermal hopping and superexchange should contribute significantly to charge transfer even in short DNA/PNA fragments. PNA is found to be more flexible than DNA, and this flexibility is predicted to produce larger rates of charge transfer.     

Molecular design of porphyrin-based nonlinear optical materials

Nonlinear optical chromophores containing (porphyrinato)Zn(II), proquinoid, and (terpyridyl)metal(II) building blocks were optimized in a library containing approximately 10(6) structures using the linear combination of atomic potentials (LCAP) methodology. We report here the library design and molecular property optimizations. Two basic structural types of large beta(0) chromophores were examined: linear and T-shaped motifs. These T-shaped geometries suggest a promising NLO chromophoric architecture for experimental investigation and further support the value of performing LCAP searches in large chemical spaces.     

Minesweeper on graphs

Minesweeper is a popular single player game. It has been shown that the Minesweeper consistency problem is NP-complete and the Minesweeper counting problem is #P-complete. In this paper, we present efficient algorithms for solving these problems for Minesweeper graphs with bounded treewidth. Our algorithms turn out to be much better than those based directly on dynamic programming. The algorithms mostly use of algebraic operations on multivariate polynomials, so that one may use existing software to implement them easily.     

The Byzantine generals strike again

Can unanimity be achieved in an unreliable distributed system? This problem was named the “Byzantine Generals Problem” by L. Lamport, R. Shostak, and M. Pease (Technical Report 54, Computer Science Laboratory, SRI International, March 1980). The results obtained in the present paper prove that unanimity is achievable in any distributed system if and only if the number of faulty processors in the system is: (1) less than one-third of the total number of processors; and (2) less than one-half of the connectivity of the system's network. In cases where unanimity is achievable, algorithms for obtaining it are given. This result forms a complete characterization of networks in the light of the Byzantine Problem.