Synthesis and biological evaluation of novel pyrazole derivatives as urease inhibitors

Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of physiological conditions. The enzyme inhibitors can interact with enzymes and block their activity towards natural substrates. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. A series of novel substituted pyrazoles 8(a-j) has been synthesized by diazotization of fluoro chloro aniline (1) and the reaction of the corresponding diazonium salt solution (2) with ethyl cyanoacetate (3) to give the intermediate, ethyl 2-((3-chloro-4-fluorophenyl) diazenyl-2- cyanoacetate (4). The intermediate is then cyclised with chloroacetonitrile (5) using triethyl amine as the base to give the final compound, ethyl 4-amino-1-(3-chloro-4-flurophenyl)-5- cyano-1H-pyrazole-3-carboxylate (6). Nucleophilic substitution group is removed from the final compound and 8(a-j) derivatives have been synthesized. All the synthesized compounds were characterized by physical data (M.P. & TLC) and spectral Data (IR & 1H NMR). The synthesized compounds were evaluated for urease-inhibition activity. Molecular docking studies were carried out for these compounds with the enzyme urease. From the observations it has been noticed that some of the compounds possesses remarkable urease-inhibitory effect

HOMOTOPY ANALYSIS METHOD TO SOLVE BOUSSINESQ EQUATIONS

In this paper, Homotopy analysis method is applied to the nonlinear coupled differential equations of classical Boussinesq system. We have applied Homotopy analysis method (HAM) for the application problems in [1, 2, 3, 4]. We have also plotted Domb-Sykes plot for the region of convergence. We have applied Pade for the HAM series to identify the singularity and reflect it in the graph. The HAM is a analytical technique which is used to solve non-linear problems to generate a convergent series. HAM gives complete freedom to choose the initial approximation of the solution, it is the auxiliary parameter h which gives us a convenient way to guarantee the convergence of homotopy series solution. It seems that more artificial degrees of freedom implies larger possibility to gain better approximations by HAM

Numerical Solution of Fredholm Integral Equations of Second Kind using Haar Wavelets

Integral equations have been one of the most important tools in several areas of science and engineering. In this paper, we use Haar wavelet method for the numerical solution of one-dimensional and two-dimensional Fredholm integral equations of second kind. The basic idea of Haar wavelet collocation method is to convert the integral equation into a system of algebraic equations that involves a finite number of variables. The numerical results are compared with the exact solution to prove the accuracy of the Haar wavelet method

Similarity Solutions of the MHD Boundary Layer Flow Past a Constant Wedge within Porous Media

The two-dimensional magnetohydrodynamic flow of a viscous fluid over a constant wedge immersed in a porous medium is studied. The flow is induced by suction/injection and also by the mainstream flow that is assumed to vary in a power-law manner with coordinate distance along the boundary. The governing nonlinear boundary layer equations have been transformed into a third-order nonlinear Falkner-Skan equation through similarity transformations. This equation has been solved analytically for a wide range of parameters involved in the study. Various results for the dimensionless velocity profiles and skin frictions are discussed for the pressure gradient parameter, Hartmann number, permeability parameter, and suction/injection. A far-field asymptotic solution is also obtained which has revealed oscillatory velocity profiles when the flow has an adverse pressure gradient. The results show that, for the positive pressure gradient and mass transfer parameters, the thickness of the boundary layer becomes thin and the flow is directed entirely towards the wedge surface whereas for negative values the solutions have very different characters. Also it is found that MHD effects on the boundary layer are exactly the same as the porous medium in which both reduce the boundary layer thickness

Clinical presentation and initial management of Black men and White men with prostate cancer in the United Kingdom: the PROCESS cohort study

Background: In the United States, Black men have a higher risk of prostate cancer and worse survival than do White men, but it is unclear whether this is because of differences in diagnosis and management. We re-examined these differences in the United Kingdom, where health care is free and unlikely to vary by socioeconomic status. Methods: This study is a population-based retrospective cohort study of men diagnosed with prostate cancer with data on ethnicity, prognostic factors, and clinical care. A Delphi panel considered the appropriateness of investigations and treatments received. Results: At diagnosis, Black men had similar clinical stage and Gleason scores but higher age-adjusted prostate-specific antigen levels (geometric mean ratio 1.41, 95% confidence interval (95% CI): 1.15-1.73). Black men underwent more investigations and were more likely to undergo radical treatment, although this was largely explained by their younger age. Even after age adjustment, Black men were more likely to undergo a bone scan (odds ratio 1.37, 95% CI: 1.05-1.80). The Delphi analysis did not suggest differential management by ethnicity. Conclusions: This UK-based study comparing Black men with White men found no evidence of differences in disease characteristics at the time of prostate cancer diagnosis, nor of under-investigation or under-treatment in Black men.6 page(s

Pathways to diagnosis for Black men and White men found to have prostate cancer: the PROCESS cohort study

Black men in England have three times the age-adjusted incidence of diagnosed prostate cancer as compared with their White counterparts. This population-based retrospective cohort study is the first UK-based investigation of whether access to diagnostic services underlies the association between race and prostate cancer. Prostate cancer was ascertained using multiple sources including hospital records. Race and factors that may influence prostate cancer diagnosis were assessed by questionnaire and hospital records review. We found that Black men were diagnosed an average of 5.1 years younger as compared with White men (P<0.001). Men of both races were comparable in their knowledge of prostate cancer, in the delays reported before presentation, and in their experience of co-morbidity and symptoms. Black men were more likely to be referred for diagnostic investigation by a hospital department (P=0.013), although general practitioners referred the large majority of men. Prostate-specific antigen levels were comparable at diagnosis, although Black men had higher levels when compared with same-age White men (P<0.001). In conclusion, we found no evidence of Black men having poorer access to diagnostic services. Differences in the run-up to diagnosis are modest and seem insufficient to explain the higher rate of prostate cancer diagnosis in Black men

Sinteza i biološko djelovanje novih supstituiranih derivata tiazolin-kinolina

5-Acyl-8-hydroxyquinoline-2-(3\u27-substituted-4\u27-aryl-2,3-dihydrothiazol-2\u27-ylide- ne)hydrazones, 5a-e to 10a-c, were prepared by the reaction of the appropriate 5-acyl-8-hydroxyquinoline-4-substituted thiosemicarbazones 3a-e and phenacyl bromides 4a-e. Structures of the new compounds were verified on the basis of spectral and elemental analyses. Twenty-eight new compounds were tested for their possible antimicrobial activities. Most of the tested compounds showed weak to moderate antibacterial activity against most of the bacterial strains used in comparison with gatifloxacin as a reference drug. The test compounds showed weak to moderate antifungal activity against tested fungi in comparison with ketoconazole as a reference drug. On the other hand, the newly synthesized compounds were tested for their anti-inflammatory effects and most of them showed good to excellent anti-inflammatory activity compared to indomethacin. Moreover, ulcerogenicity and the median lethal dose (LD50) of the most active anti-inflammatory compounds 6b and 9e were determined in mice; they were non-toxic at doses up to 400 mg kg-1 after i.p. administration.5-Acil-8-hidroksikinolin-2-(3\u27-supstituirani-4\u27-aril-2,3-dihidrotiazol-2\u27-ilid- ne)hidrazoni 5a-e do 10a-c pripravljeni su reakcijom odgovarajućih 5-acil-8-hidroksikinolin-4-supstituiranih tiosemikarbazona 3a-e i fenacil bromida 4a-e. Strukture novih spojeva potvrđene su na temelju spektralnih i elementarnih analiza. Dvadeset osam novih spojeva testirano je na potencijalno antimikrobno djelovanje. Većina spojeva pokazuje slabo do umjereno antibakterijsko djelovanje protiv većine testiranih bakterijskih sojeva u usporedbi s gatifloksacinom kao referentim lijekom, te slabo do umjereno antifungalno djelovanje protiv gljivica u usporedbi s ketokonazolom kao referentnim lijekom. Testovi na protuupalno djelovanje pokazuju da većina spojeva posjeduje dobro ili snažno protuupalno djelovanje u usporedbi s indometacinom. Ulcerogeno djelovanje i srednje letalne doze (LD50) najaktivnijih spojeva 6b i 9e određeni su na miševima. Rezultati pokazuju da su netoksični u dozama do 400 mg kg-1 nakon i.p. primjene

Prediction of progression in pTa and pT1 bladder carcinomas with p53, p16 and pRb

Currently available prognostic tools appear unable to adequately predict recurrence and progression in non muscle-invasive bladder carcinomas. We aimed to assess the prognostic value of immunohistochemical evaluation of the cell cycle markers p53, p16 and pRb. Paraffin blocks were obtained from 78 cases of pTa and pT1 transitional cell carcinomas, for which long-term follow-up was available. Representative sections were stained using antibodies against p53, p16 and pRb. Altered marker expression was found in 45, 17 and 30% of cases, respectively. Concurrent alteration of two or three markers occurred in 19% of cases, and was significantly associated with grade and stage. In univariate survival analysis, the concurrent alteration of any two markers was significantly associated with progression. The greatest risk was produced by alteration of both p53 and p16, which increased the risk of progression by 14.45 times (95% confidence interval (CI) 3.10-67.35). After adjusting for grade and stage, this risk was 7.73 (CI 1.13-52.70). The markers did not generally predict tumour recurrence, except in the 25 pT1 tumours. In these, p16 alteration was associated with a univariate risk of 2.83 (CI 1.01-7.91), and concurrent p53 and p16 alteration with a risk of 9.29 (CI 1.24-69.50). Overall, we conclude that the immunohistochemical evaluation of p53 and p16 may have independent prognostic value for disease progression, and may help guide management decisions in these tumours

QSAR studies on a number of pyrrolidin-2-one antiarrhythmic arylpiperazinyls

The activity of a number of 1-[3-(4-arylpiperazin-1-yl)propyl]pyrrolidin-2-one antiarrhythmic (AA) agents was described using the quantitative structure–activity relationship model by applying it to 33 compounds. The molecular descriptors of the AA activity were obtained by quantum chemical calculations combined with molecular modeling calculations. The resulting model explains up to 91% of the variance and it was successfully validated by four tests (LOO, LMO, external test, and Y-scrambling test). Statistical analysis shows that the AA activity of the studied compounds depends mainly on the PCR and JGI4 descriptors