Synthesis,molecular docking with COX 1& II enzyme,ADMET screening and in vivo anti-inflammatory activity of oxadiazole,thiadiazole and triazole analogs of felbinac

Based on the core structure of Felbinac drug, three series (4a–d, 5a–d and 6a–n) of five membered heterocyclic derivatives containing three heteroatoms were designed and synthesized starting from Felbinac. In the rational design of the target molecules, the biphenyl ring along with the methylene bridge of felbinac was retained while the carboxyl group was substituted with biologically active substituents like 1,2,4-triazole, 1,3,4-thiadiazole and 1,3,4-oxadiazole, with an intent to obtain novel, better and safer anti-inflammatory agents with improved efficacy. The prepared molecules were then investigated for their anti-inflammatory, ulcerogenicity and analgesic activity in experimental animals. The tested compounds exhibited varying degrees of inflammatory activity (25.21–72.87%), analgesic activity (27.50–65.24%) and severity index on gastric mucosa in the range of 0.20–0.80 in comparison to positive control felbinac (62.44%, 68.70% and 1.5, respectively). Among all the prepared compounds, 2-(biphenyl-4-ylmethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (6c) emerged as the most potent NSAID compound exhibiting the highest anti-inflammatory activity (72.87% inhibition) and analgesic activity (65.24%) along with the least severity index on gastric mucosa (0.20). Further, molecular docking on cyclooxygenase and in silico ADME-Toxicity prediction studies also supported the experimental biological results and indicated that 6c has a potential to serve as a drug candidate or lead compound for developing novel anti-inflammatory and analgesic therapeutic agent(s) with minimum toxicity on gastric mucosa.     

Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74

Macrophage migration inhibitory factor (MIF) activates CD74, which leads to severe disorders including inflammation, autoimmune diseases and cancer under pathological conditions. Molecular dynamics (MD) simulations up to one microsecond revealed dynamical correlation between a residue located at the opening of one end of the MIF solvent channel, previously thought to be a consequence of homotrimerization, and residues in a distal region responsible for CD74 activation. Experiments verified the allosteric regulatory site and identified a pathway to this site via the MIF β‐strands. The reported findings provide fundamental insights on a dynamic mechanism that controls the MIF‐induced activation of CD74.     

Design,synthesis and biological evaluation of 3-(2-aminooxazol-5-yl)-2<Emphasis Type="Italic">H</Emphasis>-chromen-2-one derivatives

Background

In view of wide range of biological activities of oxazole, a new series of oxazole analogues was synthesized and its chemical structures were confirmed by spectral data (Proton/Carbon-NMR, IR, MS etc.). The synthesized oxazole derivatives were screened for their antimicrobial and antiproliferative activities.

Results and discussion

The antimicrobial activity was performed against selected fungal and bacterial strains using tube dilution method. The antiproliferative potential was evaluated against human colorectal carcinoma (HCT116) and oestrogen- positive human breast carcinoma (MCF7) cancer cell lines using Sulforhodamine B assay and, results were compared to standard drugs, 5-fluorouracil and tamoxifen, respectively.

Conclusion

The performed antimicrobial activity indicated that compounds 3, 5, 6, 8 and 14 showed promising activity against selected microbial species. Antiproliferative screening found compound 14 to be the most potent compound against HCT116 (IC₅₀?=?71.8 µM), whereas Compound 6 was the most potent against MCF7 (IC₅₀?=?74.1 µM). Further, the molecular docking study has been carried to find out the interaction between active oxazole compounds with CDK8 (HCT116) and ER-α (MCF7) proteins indicated that compound 14 and 6 showed good dock score with better potency within the ATP binding pocket and may be used as a lead for rational drug designing of the anticancer molecule.

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Synthetic approaches toward the reserpine

Reserpine is an indole alkaloid, antipsychotic, and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms. It was first isolated in 1952 from the dried root of Rauwolfia serpentina whose molecular structure was established in 1953 and natural configuration was published in 1955. The first total synthesis of reserpine was reported by Woodward in 1958. This review article updates current multistep synthetic approaches toward the reserpine natural product and its analogues.     

Kinetic spectrophotometric analysis of pantoprazole in commercial dosage forms.

A kinetic spectrophotometric method has been developed which is based on the oxidation of pantoprazole with Fe(III) in sulfuric acid medium. Fe(III) subsequently reduces to Fe(II), which is coupled with potassium ferricyanide to form Prussian blue. The reaction is followed spectrophotometrically by measuring the increase in absorbance with time (1-8 min) at 725 nm. The initial rate method is adopted for constructing the calibration graph, which is linear in the concentration range of 5-90 microg ml(-1). The regression analysis yields the calibration equation, nu = 3.467 x 10(-6) + 4.356 x 10(-5)C. The limits of detection and quantitation are 1.46 and 4.43 microg ml(-1), respectively. The proposed method was optimized and validated both statistically and through recovery studies. The experimental true bias of all samples is < +/-2.0%. The method has been successfully applied to the determination of pantoprazole in pharmaceutical preparations.     

CsF-Celite, an Efficient Solid State Reagent for the Syntheses of Thioesters and Thioethers

Coupling reactions of a number of aliphatic, aromatic, and heterocyclic compounds bearing an acidic hydrogen atom attached to sulfur, with alkyl, acyl, benzyl, or benzoyl halides in acetonitrile with cesium fluoride-Celite are described. This procedure is convenient, efficient, and practical for the preparation of thioethers and thioesters.     

Ion exchange of 90Sr and 137Cs into 1‐vinyl‐2‐pyrrolidone–divinylbenzene cation‐exchange resin

Radiotracer batch ion‐exchange experiments were employed to investigate the uptake of ⁹⁰Sr and ¹³⁷Cs radioisotopes by various cation‐exchanged forms of a 30% cross‐linked macroporous 1‐vinyl‐2‐pyrrolidone–divinylbenzene cation‐exchange resin with 1.37 ml g^?1 pore volume, 0.0232 µm pore diameter and 271.2 m² g^?1 surface area. The uptake of ⁹⁰Sr and ¹³⁷Cs was determined by taking liquid aliquots at various time intervals from solutions over solids. The volume‐to‐solid ratio was kept at 200. The results of kinetic experiments for the carrier‐free ⁹⁰Sr and ¹³⁷Cs were evident in all cationic forms of the resin. The percentage uptake and distribution coefficient K_d values with carrier (0.005 M SrCl₂ and 0.01 M CsCl) concentrations were also determined, and the best results were obtained from the Li⁺ and H⁺ forms of the resin. Cerenkov counting (β^?‐counting) was used to observe the initial and final radioactivity in the liquid phase. All the experiments were carried out at room temperature and the radioactivity in each case was corrected for the background counts. Copyright © 2005 John Wiley & Sons, Ltd.     

Estimation de la fonction de survie sous biais de longueur pour des risques concurrents et proportionnels

Consider a population of individuals who experience two causes of death. We observe the ones alive at time t₀ and follow them until death. Given this length bias sample, we propose an estimator of the survival function of ‘initial survival times’ (i.e., for the entire population) under the assumption of proportional hazards for the two causes of death. The large sample behaviour of our estimator is also studied. To cite this article: J.-Y. Dauxois et al., C. R. Acad. Sci. Paris, Ser. I 337 (2003).     

Poly[(R)‐3‐hydroxybutyrate)]/poly(styrene) blends compatibilized with the relevant block copolymer

A novel triblock copolymer PS–PHB–PS based on the microbial polyester Poly[(R)‐3‐hydroxybutyrate)] (PHB) and poly(styrene) (PS) was prepared to be used as compatibilizer for the corresponding PHB/PS blends. It was prepared in a three‐step procedure consisting of (i) transesterification reaction between ethylene glycol and a high‐molecular‐weight PHB, (ii) synthesis of bromo‐terminated PHB macroinitiator, and (iii) atom transfer radical polymerization polymerization of styrene initiated by the PHB‐based macroinitiator. Fourier transform infrared, gel permeation chromatography, ¹H‐, and ¹³C‐NMR spectroscopies were used to determine the molecular structure and/or end‐group functionalities at each step of the procedure. Although thermogravimetric analysis showed that the block copolymer underwent a stepwise thermal degradation and had better thermal stability than their respective homopolymers, differential scanning calorimetry displayed that the PHB block in the copolymer could not crystallize, and thus generating a total amorphous structure. Atomic force microscopy images indicated that the block copolymer was phase segregated in a well‐defined morphological structure with nanodomain size of ～40 nm. Contact angle measurements proved that the wettability properties of the block copolymer were in between those of the PHB and PS homopolymers. Blends analyzed for their morphology and thermal properties showed good miscibility and had well‐defined morphological features. Polymer blends exhibited lower crystallinity and decreased stiffness which was proportional to the amount of compatibilizer content in the blends. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

The kinetics of electron transfer reaction of methylene green and titanium trichloride in different solvents

The kinetics of the electron transfer reaction of methylene green and titanium trichloride was investigated in different solvents by spectrophotometry at different temperatures. The the reaction rate was determined by monitoring the absorbance as a function of time at λ_max 655 nm. The reaction is pseudo-first order, dependent only on the concentration of titanium trichloride at a fixed concentration of methylene green.