Mycobacterial CYP121 as a target for anti-TB drug discovery

Despite the introduction of the first line treatment regimen forty years ago and the continuous trials since that time to introduce new regimens, tuberculosis (TB) is considered to be the cause of considerable mortality worldwide. Recent research highlighted the Mycobacterium tuberculosis (Mtb)CYP450s as potential drug targets. This article reviews mycobacterial CYP121 as a target for anti-TB drug discovery

DESIGN, SYNTHESIS AND COX1/2 INHIBITORY ACTIVITY OF NEW QUINAZOLINE-5-ONE DERIVATIVES

A new series of 1-(4-Acetylphenyl)-7,7-dimethyl-3-(substitutedphenyl)-1,2,3,4,7,8-octahydroquinazolin-5(6H)-ones (6-15) were synthesized and tested against COX-1 and COX-2 enzymes. Those compounds exhibited strong interaction at the COX-2 binding site and poor interaction at the COX-1 active site. Subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assay; most of the compounds especially compounds 6, 7, 12, 13, and 16 exhibited potent anti-inflammatory effects, selective COX-2 inhibition, with half-maximal inhibitor concentration (IC50) values of 0.22–1.42 μM and selectivity index (SI) values of 6.16–14.18 compared with celecoxib (IC50 = 0.05 μM and COX-2 SI: 296), diclofenac (IC50 = 0.8 μM and COX-2 SI: 4.87), and indomethacin (IC50 = 0.49 μM and COX-2 SI: 0.08) as reference drugs. Docking study has been carried out to confirm the binding affinity and selectivity of the most active compound (compound 6) to COX-2 enzyme

Structural and Optical Properties of Varies Thickness of Znte Nanoparticle

ZnTe thin films of different thicknesses were deposited onto glass substrates for optical devices applications. Xray diffractogram of different thicknesses for ZnTe films are measured and their patterns exhibits polycrystalline nature with a preferential orientation along the (111) plane. X-ray diffraction techniques have been employed to determine the microstructure parameters, both crystallite size and microstrain. Film thickness and the optical constants of ZnTe films were calculated based on the measured transmittance spectral data using Swanepole’s method in the wavelength range 400–2500 nm. The refractive index n and absorption index k were calculated, and the refractive index exhibits a normal dispersion. The refractive index could be extrapolated by Cauchy dispersion relationship over the whole spectra range, which extended from 400 to 2500 nm. The optical band gap can be calculated in strong absorption region and displays an allowed direct transition. Both the refractive index and the band gap increase with the increase film thickness, thus ZnTe/glass substrates are good candidates in optoelectronic devices

Structural and Optical Properties of Varies Thickness of Znte Nanoparticle

ZnTe thin films of different thicknesses were deposited onto glass substrates for optical devices applications. Xray diffractogram of different thicknesses for ZnTe films are measured and their patterns exhibits polycrystalline nature with a preferential orientation along the (111) plane. X-ray diffraction techniques have been employed to determine themicrostructure parameters, both crystallite size and microstrain. Film thickness and the optical constants of ZnTe films were calculated based on the measured transmittance spectral data using Swanepole’s method in the wavelength range 400–2500 nm. The refractive index n and absorption index k were calculated and the refractive index exhibits a normal dispersion. The refractive index could be extrapolated by Cauchy dispersion relationship over the whole spectra range, which extended from 400 to 2500 nm. The optical band gap can be calculated in strong absorption region and displays an allowed direct transition. Both the refractive index and the band gap increase with the increase film thickness, thus ZnTe/glass substrates are good candidates in optoelectronic devices.Keywords: ZnTe, thin film, cry crystallitze size; microstrain; optical constants

EFFECT METALORGANIC FRAMEWORK ON THE ELECTROCHEMICAL PERFORMANCE OF LiCoPO4

We coated the LiCoPO4 by Mteal-organic framework. The LiCoPO4/C@Mil-88 and LiCoPO4/C@UiO-66 were synthesized via the microwave-assisted solvothermal route, and 100, 147 mA h/ g discharge capacity, respectively, was obtained in the first cycle.A.M. Aboraia and AVS acknowledge RFBR for financial support according to the project No 19-32-90214

Mycobacterial CYP121 as a target for anti-TB drug discovery

Despite the introduction of the first line treatment regimen forty years ago and the continuous trials since that time to introduce new regimens, tuberculosis (TB) is considered to be the cause of considerable mortality worldwide. Recent research highlighted the Mycobacterium tuberculosis (Mtb)CYP450s as potential drug targets. This article reviews mycobacterial CYP121 as a target for anti-TB drug discovery

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis

Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 N4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using in silico, in vitro, and in vivo approaches. Several compounds displayed interesting activities against both Gram-negative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic in vitro assays. Phenotypic analysis of both Escherichia coli and Bacillus subtilis confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the B. subtilis cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones

Frequentist Interpretation of Probability

Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target

Development of a versatile laboratory experiment to teach the metabolic transformation of hydrolysis

In this paper we describe an easy, reliable, versatile and inexpensive laboratory experiment to teach the metabolic transformation of hydrolysis to Pharmacy students. The experiment does not require the sacrifice of any experimental animal, or any work with organs or tissues, and so can be implemented in a typical university chemistry laboratory. We used acetylsalicylic acid (ASA), hexyl salicylate (HS) and two enzymes, a lipase and an esterase. Since both ASS and HS liberate salicylic acid (SA) upon hydrolysis, students can evaluate the different enzymatic transformations by monitoring the amount of SA liberated. The learning outcomes are an enhanced student understanding of: (1) the process of hydrolysis; (2) the application of enzymatic transformations of molecules from food to xenobiotics; (3) the differences between the general specificity of substrate of both enzymes; (4) the concepts of the lipophilic pocket; (5) the catalytic triad and its regioselectivity in relation to the ester bond. A questionnaire was administered to participating students at three points in time: at the beginning of the module, after enzymatic hydrolysis was taught in class, and after the laboratory experiment. From an analysis of the questionnaire data we conclude that this practical helped Pharmacy students to understand these concepts