Preparation and Characterization of New 1,3,5-Trisubstituted-2-Pyrazolines Derivative for their Anti-Inflammatory Activity

The objective of the paper was to design, synthesis and characterization of new 1,3,5-trisubstituted-2-pyrazolines derivative and evaluate for anti-inflammatory potential. The 1,3,5-tri-substituted-2-pyrazolines derivatives has been synthesized by the reaction of chalcone derivatives with 4-hydrazinylbenzene sulfonamide hydrochloride and phenyl hydrazine hydrochloride. Total Sixteen compounds has been synthesized and characterized by the IR, 1HNMR and mass spectral analysis. Proposed compounds have been evaluated for anti-inflammatory activity. Anti-inflammatory activity of the compounds carried out by two animal model i.e. Carrageenan induced, paw edema in rats and Inhibition of formalin induced paw edema in rats. Anti-inflammatory activity of the compounds C7, C8 and C2 were shown 98.26, 92.77 and 96.24 percentages of inhibition and compounds D7, D8 and D2 were shown 81.50, 83.81 and 78.32 percentages of inhibition as compared to the standard drug Diclofenac at 10 mg/kg was inhibit the inflammation 99.42 % after 6h. These result is a evident that synthesized compounds show relevant degree of anti-inflammatory activity as compared to the standard drug. It is also concluded that the presence of SO2NH2 group, Cl, CH3, OCH3 and N(CH3)2 group may provide the active compounds when attached to the pyrazoline group. But the addition of OH, Br and no substitution in phenyl ring may diminish the activity.

Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.

An efficient multicomponent synthesis of 1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione derivatives and evaluation of their α-amylase and α-glucosidase inhibitory activity

In this paper, we report the synthesis of novel 1 H-pyrano[2,3- d]pyrimidine-2,4(3 H,5 H)-dione derivatives 5(a–j) by a facile multicomponent reaction. The structures of all the newly synthesized compounds were characterized by different spectroscopic techniques including infrared, nuclear magnetic resonance (1H and 13C) and mass spectral analysis. All the new compounds were assessed for their in vitro α-amylase and α-glucosidase enzyme inhibitory potential. The results of the assays revealed that all compounds showed different enzyme inhibition activities. The concentration required to inhibit enzyme activity is less in the case of α-glucosidases than for α-amylases, that is, the synthesized compounds are more potent in arresting α-glucosidase enzyme activity.

1,2,4-triazoles Clubbed Pyrimidine Compounds with Synthesis, Antimicrobial, Antituberculosis, Antimalarial, and Anti-protozoal Studies

: Triazoles are famous as an antifungal agent. Itraconazole and fluconazole are the best examples of antifungal drugs available in the market, which consist an active triazole moiety. Pyrimidines are also bioactive molecules which shows multiple bioactivity. It’s an effort to synthesize pyrimidine clubbed triazole to enhance bioactivity. To synthesize new active pyrimidine clubbed triazole biomolecule and to evaluate these new products for better drug potential as antimicrobial, an-tituberculosis, antimalarial, and anti-protozoal. N-[4-(substituted phenyl)-6-(substituted aryl) pyrimidine-2-yl]-2-[(4H-1,2,4-triazol-4-yl)amino]acetamide(3A-J) were synthesized by different method as cyclization, condensation, purification and crystallization. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral analysis and screened for antibacterial, antifungal, anti-tuberculosis, antimalarial, and anti-protozoal activities. These com-pounds satisfied the bioactive response and simple way for the synthesis.

Syntheses of 3,3-Disubstituted Dihydrobenzofurans, Indolines, Indolinones and Isochromanes by Palladium-Catalyzed Tandem Reaction Using Pd(PPh3)2Cl2/(±)-BINAP as a Catalytic System

A general procedure for the tandem arylation reaction of arylbromide with heteroaryl compounds was developed by using Pd(PPh3)2Cl2/(±)-BINAP (1,1′-Binaphthalene-2,2′-diylbis (diphenylphosphane)) as catalytic system. Both sulphur- and oxygen-containing heterocycles were also employed as an efficient reagent for arylation, which gave moderate to excellent yields with moderate to good regioselectivities (5:1 to > 20:1 ir (isomer ratio)). Except for dihydrobenzofurans, indolines and indolinones, this type of tandem reaction was also expanded to synthesize isochromanes. The synthesized new compounds were well characterized through different spectroscopic techniques, such as 1H and 13C NMR (nuclear magnetic resonance), and mass spectral analysis.

Canonical Notch ligands and Fringes have distinct effects on NOTCH1 and NOTCH2

Notch signaling is a cellular pathway regulating cell-fate determination and adult tissue homeostasis. Little is known about how canonical Notch ligands or Fringe enzymes differentially affect NOTCH1 and NOTCH2. Using cell-based Notch signaling and ligand-binding assays, we evaluated differences in NOTCH1 and NOTCH2 responses to Delta-like (DLL) and Jagged (JAG) family members and the extent to which Fringe enzymes modulate their activity. In the absence of Fringes, DLL4–NOTCH1 activation was more than twice that of DLL4–NOTCH2, whereas all other ligands activated NOTCH2 similarly or slightly more than NOTCH1. However, NOTCH2 showed less sensitivity to the Fringes. Lunatic fringe (LFNG) enhanced NOTCH2 activation by DLL1 and -4, and Manic fringe (MFNG) inhibited NOTCH2 activation by JAG1 and -2. Mass spectral analysis showed that O-fucose occurred at high stoichiometry at most consensus sequences of NOTCH2 and that the Fringe enzymes modified more O-fucose sites of NOTCH2 compared with NOTCH1. Mutagenesis studies showed that LFNG modification of O-fucose on EGF8 and -12 of NOTCH2 was responsible for enhancement of DLL1–NOTCH2 activation, similar to previous reports for NOTCH1. In contrast to NOTCH1, a single O-fucose site mutant that substantially blocked the ability of MFNG to inhibit NOTCH2 activation by JAG1 could not be identified. Interestingly, elimination of the O-fucose site on EGF12 allowed LFNG to inhibit JAG1-NOTCH2 activation, and O-fucosylation on EGF9 was important for trafficking of both NOTCH1 and NOTCH2. Together, these studies provide new insights into the differential regulation of NOTCH1 and NOTCH2 by Notch ligands and Fringe enzymes.