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

Abstract

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 IC 50 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 IC 50 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.

Ligand‐Guided Investigation of a Series of Formamidine‐Based Thiuram Disulfides as Potential Dual‐Inhibitors of COX‐1and COX‐2

“…Compounds 1 and 4 exhibited potential dual protein selectivity towards COX1 and COX2. COX1 and COX2 are protein targets in cancer‐related inflammation [30,31] . COX 1 and COX 2 X‐ray crystal structures were obtained from the protein data bank, [32] with PDB codes 5WBE and 5F19, respectively.…”

“…COX1 and COX2 are protein targets in cancer-related inflammation. [30,31] COX 1 and COX 2 X-ray crystal structures were obtained from the protein data bank, [32] with PDB codes 5WBE and 5F19, respectively. System preparations and visualizations were carried out on Chimera.…”

Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFRWtand VEGFR-2 inhibitors with apoptotic inducers

“…Toxicological studies. The toxicity prediction for the most active compound and positive control was predicted using two web tools, namely, Protox II (https://tox-new.charite.de/ protox_II/, access 1/2/2023) 54,55 and pkCSM (https:// biosig.lab.uq.edu.au/pkcsm/prediction, access 1/2/2023) described previously. 56,57 The promising 2-oxo-1 ′ H-spiroindoline-3,4 ′ -pyridine derivative 7 revealed a median lethal dose (LD 50 = 1000 mg kg −1 and belongs to toxicity class IV) higher than Doxorubicin (LD 50 = 205 mg kg −1 , class III), Erlotinib (LD 50 = 125 mg kg −1 , class III), and Sorafenib (LD 50 = 800 mg kg −1 , class IV).…”

Small Molecules as Anti‐inflammatory Agents: Molecular Mechanisms and Heterocycles as Inhibitors of Signaling Pathways

“…[142] Though the literature evidence the design, synthesis, and potent anti-inflammatory activity of several pyrazole analogs, still, there is a need for the development of an anti-inflammatory drug containing this scaffold with low side effects and less or no toxicity compared to the available drug celecoxib. [143][144][145][146]…”