Searching for effective and selective anti‐inflammatory agents, our study involved designing and synthesizing new pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives 4–11. The structures of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using in silico docking simulation inside the active sites of four proteins classified as two cyclooxygenases (COX)‐1 (PDB: 3KK6 and 4OIZ) and two COX‐2 (PBD: 1CX2 and 3LN1). Among them, six derivatives 4c, 5b, 6a, 7a, 7b, and 10b displayed the highest binding energy. These derivatives were evaluated for their in vitro COX‐1 and COX‐2 inhibitory activities and their selectivity indexes were calculated. Additionally, these derivatives displayed IC50 values ranging between 4.909 ± 0.25 and 57.53 ± 2.91 µM, and 3.289 ± 0.14 and 124 ± 5.32 µM, against COX‐1 and COX‐2, respectively. Furthermore, the tested derivatives were found to have selective inhibitory activity on the COX‐2 enzyme. Surprisingly, the two pyrazole derivatives 4c and 5b were found to be the most active, with IC50 values of 9.835 ± 0.50 and 4.909 ± 0.25 µM and 4.597 ± 0.20 and 3.289 ±  0.14 µM compared with meloxicam (1.879 ± 0.1 and 5.409 ±  0.23 µM) and celecoxib (5.439 ± 0.28 and 2.164 ± 0.09 µM) against COX‐1/‐2, respectively. Besides, two pyrazole derivatives, 4c and 5b, displayed a COX‐1/COX‐2 SI of 2.14 and 1.49. Computational techniques such as molecular docking, density function theory (DFT) calculation, and chemical absorption, distribution, metabolism, excretion, and toxicity evaluation were applied to explain the molecules’ binding mode, chemical nature, drug likeness, and toxicity prediction.

Discovery of novel pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives as cyclooxygenase inhibitors (COX‐1 and COX‐2) using molecular modeling simulation

Synthesis of thiophene derivatives: Substituent effect, Antioxidant activity, Cyclic voltammetry, Molecular Docking, DFT, and TD-DFT Calculations

Searching for new compounds with anti-inflammatory properties is a significant target since inflammation is a major cause of pain. A series of pyrazole, imidazopyrazolone, and pyrazolopyrimidine derivatives were designed and synthesized by reaction of 3,5-diamino-1H-pyrazole derivative with cyclic and acyclic carbonyl reagents. The structure of the newly synthesized derivatives were fully characterized using different spectroscopic data and elemental analysis, and therefore, evaluated as COX-2 inhibitors. The in vitro COX-2 activity of the tested derivatives 2–13 displayed moderate to good potency with two derivatives 8 and 13 that exhibiting high potency to COX-2 with IC50 values of 5.68 ± 0.08 and 3.37 ± 0.07 μM compared with celecoxib (IC50 = 3.60 ± 0.07 μM) and meloxicam (IC50 = 7.58 ± 0.13 μM). Furthermore, the most active pyrazolo[1,5-a]pyrimidine derivatives 8 and 13 were evaluated to measure the levels of pro-inflammatory proteins such as TNF-α and IL-6 using qRT-PCR in RAW264.7 cells, and the results showed down-regulation of two immunomodulatory proteins. Surprisingly, these derivatives 8 and 13 revealed a decrease in IL-6 level with inhibition percentages of 65.8 and 70.3%, respectively, compared with celecoxib (% = 76.8). Further, compounds 8 and 13 can regulate and suppress the TNF-α with percentage inhibition of 63.1 and 59.2% to controls, while celecoxib displayed an inhibition percentage of 72.7. The Quantum chemical calculation was conducted, and data explained the structural features crucial to the activity. The molecular docking simulation and ADMET predictions revealed that the most active derivatives have good binding affinity, possess appropriate drug-likeness properties and low toxicity profiles. Finally, compounds 8 and 13 demonstrated COX-2 inhibitors with α-TNF and IL-6 suppression capabilities as a dual-action strategy to get more effective treatment. 

Development of novel pyrazole, imidazo[1,2-b]pyrazole, and pyrazolo[1,5-a]pyrimidine derivatives as a new class of COX-2 inhibitors with immunomodulatory potential.

Synthesis of Biologically Active α-Tetralone Condensate: Growth of Single Crystal, Characterization by Experimental and Simulation Methods

Spectroscopic, computational DFT, in vitro, and molecular docking investigations of newly isolated 2, 3, 9, and 10-tetrahydroacridin-3-one from the methanolic extract of nilavembu kudineer chooranam

Novel quinoxaline derivatives of 2, 3-diphenylquinoxaline-6-carbaldehyde and 4, 4′-(6-methylquinoxaline-2,3-diyl)bis(N,N-diphenylaniline): Synthesis, structural, DFT-computational, molecular docking, antibacterial, antioxidant, and anticancer studies

G.R. Ramkumaar

Papers

Novel quinoxaline derivatives of 2, 3-diphenylquinoxaline-6-carbaldehyde and 4, 4′-(6-methylquinoxaline-2,3-diyl)bis(N,N-diphenylaniline): Synthesis, structural, DFT-computational, molecular docking, antibacterial, antioxidant, and anticancer studies