Discovery of novel aminophosphonate derivatives containing pyrazole moiety as potential selective COX-2 inhibitors.

Cyclooxygenase is critical for maintaining physiological functions, whereas overexpression of COX-2 was closely implicated in various cancers. In this study, a series of novel aminophosphonate derivatives containing pyrazole moiety were synthesized with their anti-cancer activity evaluated. In vitro assays of the target compounds showed that Z21 displayed excellent COX-2 inhibitory activity against COX-2 (IC50 = 0.22 ± 0.04 µM) and anti-proliferative activity against MCF-7 cell (IC50 = 4.37 ± 0.49 µM). The apoptosis induction of compound Z21 was confirmed by flow cytometry and polymerase chain reaction. Further investigation demonstrated that compound Z21 induced apoptosis of MCF-7 cells through a mitochondrion-dependent pathway and involved cell-cycle arrest in G2 phase. Overall, these results provided some new insights into the design of therapeutic drugs for COX-2 inhibitors and indicated the connection between selective COX-2 inhibition and the anti-tumor activity.

Discovery of New Schiff Bases Tethered Pyrazole Moiety: Design, Synthesis, Biological Evaluation, and Molecular Docking Study as Dual Targeting DHFR/DNA Gyrase Inhibitors with Immunomodulatory Activity.

A series of Bis-pyrazole Schiff bases (6a-d and 7a-d) and mono-pyrazole Schiff bases (8a-d and 9a-d) were designed and synthesized through the reaction of 5-aminopyrazoles 1a-d with aldehydes 2-5 using mild reaction condition with a good yield percentage. The chemical structure of newly formed Schiff bases tethered pyrazole core was confirmed based on spectral and experimental data. All the newly formed pyrazole Schiff bases were evaluated against eight pathogens (Gram-positive, Gram-negative, and fungi). The result exhibited that, most of them have good and broad activities. Among those, only six Schiff bases (6b, 7b, 7c, 8a, 8d, and 9b) displayed MIC values (0.97-62.5 µg/mL) compared to Tetracycline (15.62-62.5 µg/mL) and Amphotericin B (15.62-31.25 µg/mL), MBC values (1.94-87.5 µg/mL) and selectivity to tumor cell than normal cells. Immunomodulatory activities showed that the promising Schiff bases increase the immunomodulator effect of defense cell and the Schiff base 8a is the highest one by (Intra. killing activity = 136.5 ± 0.3%) having a pyrazole moiety as well as amide function (O=C-NH2) and piperidinyl core. Furthermore, the most potent one exhibited broad activity depending on both MIC and MBC values. Moreover, to study the mechanism of these pyrazole Schiff bases, two active Schiff bases 8a and 9b from six derivatives were introduced to study the enzyme assay as dihydrofolate reductase (DHFR) on E. coli organism and DNA gyrase with two different organisms, S. aureus and B. subtilis, to determine the inhibitory activities with lower values in the case of DNA gyrase (8a and 9b) or nearly as DHFR compound 9b, while pyrazole 8a showed excellent inhibitory against all enzyme assay. The molecular docking study against dihydrofolate reductase and DNA gyrase were performed to study the binding between active site in the pocket with the two Schiff bases (8a and 9b) that exhibited good binding affinity with different bond types as H-bonding, aren-aren, and arene-cation interaction as well as study the physicochemical and pharmacokinetic properties of the two active Schiff bases 8a and 9b.

Facile and diastereoselective synthesis of 3,2'-spiropyrrolidine-oxindoles derivatives, their molecular docking and antiproliferative activities.

In the present study, a series of novel highly functionalized spiropyrrolidine-oxindoles have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide formed from isatin and various amino acids such as sarcosine, proline and thioproline with the dipolarophile (E)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(1H-indole-3-carbonyl)acrylonitrile under optimized conditions. All the synthesized compounds were evaluated for their antimicrobial activity and shown significant activity.