Synthesis and Anti-Cancer Activity of New Pyrazolinyl-Indole Derivatives: Pharmacophoric Interactions and Docking Studies for Identifying New EGFR Inhibitors

Newly designed series of indole-containing pyrazole analogs, pyrazolinylindoles, were synthesized, and their structures were confirmed based on the spectral data of the ¹H NMR, ¹³C NMR, and HR-MS analyses. Preliminary anti-cancer activity testings were carried out by the National Cancer Institute, United States of America (NCI, USA). Compounds HD02, HD05, and HD12 demonstrated remarkable cytotoxic activities against nine categories of cancer types based cell line panels which included leukemia, colon, breast, melanoma, lungs, renal, prostate, CNS, and ovarian cancer cell lines. The highest cytotoxic effects were exhibited by the compounds HD02 [1-(5-(1-H-indol-3-yl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenylethanone], HD05 [1-(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenoxyethanone], and HD12 [(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone] against some of the 56 types of NCI-based cell lines in different panels. Compound HD05 showed the maximum range of cancer cell growth inhibitions against all categories of the cell lines in all nine panels. On average, in comparison to the referral standard, imatinib, at a dose level of 10 µM, the HD05 showed significant activity against leukemia in the range of 78.76%, as compared to the imatinib at 9% of cancer cells’ growth inhibitions. Molecular docking simulation studies were performed in silico on the epidermal growth factor receptor (EGFR) tyrosine kinase, in order to validate the activity.     

Reactions with Thiazolo[3,2-b]-s-triazol-3(2H)-ones

5-Aryl-3-carboxymethylthio-1,2,4-triazoles 2 are cyclised to 6-arylthiazolo[3,2-b]-s-triazol-3(2H)-ones 3 . This structural assignment has been based on IR and NMR spectra. 2-Arylmethylene-6-arylthiazolo[3,2-b]-s-triazol-3(2H)-ones 7 were prepared by several methods. Compounds 3 coupled with diazotised anilines to give 2,3-dihydro-6-arylthiazolo[3,2-b]-s-triazole-2,3-dione 2-arylhydrazones 8 . The action of amines on 3a opens the thiazolone ring with the formation of substituted (5-phenyltriazol-3-ylthio)-acetamides 9 .     

Discrete-time implementation of high-gain observers for numerical differentiation

High-gain observers have been used in non-linear control to estimate derivatives of the output. In this paper, we study discrete-time implementation of high-gain observers and their use as numerical differentiators, in noise-free as well as noisy measurements. We show that discretization using the bilinear transformation method gives better results than other discretization methods. We also show that many of the available numerical differentiators are special cases of the bilinear discrete-time equivalents of full-order or reduced-order high-gain observers.     

Simulation of the urban climate variations in connection with the transformations of the city of Nantes since the 17th century

The paper seeks to quantify the effect of urban politics on the microclimate of the city of Nantes (France), in particular those initiated by the sanitarians in the mid-19th century to find a remedy for the insalubrity that had been developing with urban densification since the late 17th century. Intensive historical research was first carried out in order to define and date the major transformations undergone by the city, its structure (densification, then widening of the streets, filling of water courses), the lifestyle habits (heating) or the building practices (appearance of stone and paving, higher buildings, insulation). This led to the definition of 5 characteristic states of the city, in 1680, 1756, 1835, 1880 and 1945.     

Turbulent boundary layers: is the wall falling or merely wobbling?

A quick passage through five centuries of turbulence research highlights the major milestones. The more recent cornerstones include Kolmogorov??s equilibrium theory of turbulence spectrum, the universal logarithmic law of wall-bounded flows, and the proliferation of direct numerical simulations. Evidence of recent fault lines in all three major achievements is presented, but also novel remedies as well as a few contemporary accomplishments are pointed out.     

Comments on the security of Chen’s authenticated encryption scheme

Chen (Computers and Electrical Engineering, vol. 30, 2004) illustrated that Tseng et al.’s authenticated encryption schemes, with message linkages for message flows, do not achieve their claimed integrity and authenticity properties. Furthermore, Chen presented some modified schemes to repair these flaws. In this paper, we show that the modified schemes proposed by Chen are not secure. In particular, we present an attack that allows a dishonest referee, in case of a dispute, to decrypt all the future and past authenticated ciphertext between the contended parties. We also present a simple fix to prevent this attack.     

Crypt analysis of two time pads in case of compressed speech

Keystream reuse, also known as the two time pad problem, is a well known weakness in stream ciphers. The implementers of the cryptographic algorithms are still underestimating this threat. The keystream reuse exploitation techniques presented so far assume the underlying plaintext to be textual data and all the heuristics presented previously are based on the language characteristics of the underlying text based data, which fail when compression is applied on the plaintext before encryption. This paper presents exploitation techniques for two time pads in case of stream ciphered digitized and compressed speech signals. In this paper we show that how an adversary can automatically recover the digitized speech signals encrypted under the same keystream provided the language (e.g. English) and digital encoding/compression scheme details of the underlying speech signals are known. Our technique of cryptanalysis is based on the modeling of the speech parameters by exploiting the inter frame correlations between each components of the speech vectors in different frames and then using these models to decode the two speech signals in the keystream reuse scenario. The technique is flexible enough to incorporate all modern speech coding schemes based on parameter or hybrid encoding and compression techniques. The simulation experiments have showed promising results for most of the present day speech digitization and compression techniques.     

Friction model for friction stir welding process simulation: Calibrations from welding experiments

The accurate 3D finite element simulation of the Friction Stir Welding (FSW) process requires a proper knowledge of both material and interface behaviors, but friction, the key phenomenon of this process, is quite difficult to model and identify. According to the extreme encountered conditions and the highly coupled nature of the material flow, simple tribological tests are not representative enough, so the welding process itself has been utilized in most analyses of the literature, although its complexity has led to use simplified numerical models and approaches. The recent development of more accurate 3D simulation software, which allows modeling the entire complexity of the FSW process, makes it possible to follow a much more rigorous inverse analysis (or calibration) approach. FSW trials are conducted on an Al 6061 aluminum plate with an unthreaded concave tool. Forces and tool temperatures are accurately recorded at steady welding state, for different welding speeds. The numerical simulations are based on an Arbitrary Lagrangian Eulerian (ALE) formulation that has been implemented in the Forge3^® F.E. software. The main feature of the numerical approach is to accurately compute the contact and frictional surface between the plate and the tool. A first study using Norton's friction model show the great sensitivity of welding forces and tool temperatures to friction coefficients, the need to take into account the changes brought to the contact surface by slight friction variations (thanks to the ALE formulation), the possibility to get very accurate calibrations on forces, and the impossibility to properly render the tool temperature profile. On the other hand, the use of Coulomb's friction model allows obtaining realistic temperature profiles and so calibrating a friction coefficient that offers an excellent agreement with experiments, on forces as much as on tool temperatures, for various welding speeds.