Synthesis, characterization, molecular docking, analgesic, antiplatelet and anticoagulant effects of dibenzylidene ketone derivatives

Abstract

In this study dibenzylidene ketone derivatives (2E,5E)-2-(4-methoxybenzylidene)-5-(4-nitrobenzylidene) cyclopentanone (AK-1a) and (1E,4E)-4-(4-nitrobenzylidene)-1-(4-nitrophenyl) oct-1-en-3-one (AK-2a) were newly synthesized, inspired from curcuminoids natural origin. Novel scheme was used for synthesis of AK-1a and AK-2a. The synthesized compounds were characterized by spectroscopic techniques. AK-1a and AK-2a showed high computational affinities (E-value > − 9.0 kcal/mol) against cyclooxygenase-1, cyclooxygenase-2, proteinase-activated receptor 1 and vitamin K epoxide reductase. AK-1a and AK-2a showed moderate docking affinities (E-value > − 8.0 kcal/mol) against mu receptor, kappa receptor, delta receptor, human capsaicin receptor, glycoprotein IIb/IIIa, prostacyclin receptor I2, antithrombin-III, factor-II and factor-X. AK-1a and AK-2a showed lower affinities (E-value > − 7.0 kcal/mol) against purinoceptor-3, glycoprotein-VI and purinergic receptor P2Y12. In analgesic activity, AK-1a and AK-2a decreased numbers of acetic acid-induced writhes (P < 0.001 vs. saline group) in mice. AK-1a and AK-2a significantly prolonged the latency time of mice (P < 0.05, P < 0.01 and P < 0.001 vs. saline group) in hotplate assay. AK-1a and AK-2a inhibited arachidonic acid and adenosine diphosphate induced platelet aggregation with IC50 values of 65.2, 37.7, 750.4 and 422 µM respectively. At 30, 100, 300 and 1000 µM concentrations, AK-1a and AK-2a increased plasma recalcification time (P < 0.001 and P < 0.001 vs. saline group) respectively. At 100, 300 and 1000 µg/kg doses, AK-1a and AK-2a effectively prolonged bleeding time (P < 0.001 and P < 0.01 vs. saline group) respectively. Thus in-silico, in-vitro and in-vivo investigation of AK-1a and AK-2a reports their analgesic, antiplatelet and anticoagulant actions.

Attenuation of Spatial Memory in 5xFAD Mice by Halting Cholinesterases, Oxidative Stress and Neuroinflammation Using a Cyclopentanone Derivative

“…Cyclopentanone derivatives have been reported to exhibit anti-inflammatory, analgesic, antioxidant, anticoagulant, anti- AChE , and anti- BChE activities [ 8 , 9 , 10 , 11 ]. Following up on this perspective the cyclopentanone derivative 2-(hydroxy-(3-nitrophenyl)methyl)cyclopentanone (3NCP, Figure 1 ) [ 12 ] was evaluated as a possible potential candidate against AD.…”

Chemical and Pharmacological Profiling of Wrightia coccinea (Roxb. Ex Hornem.) Sims Focusing Antioxidant, Cytotoxic, Antidiarrheal, Hypoglycemic, and Analgesic Properties

“…The current study reported the isolation of four compounds from W. coccinea including 3β-acetyloxy-olean-12-en-28-ol, wrightiadione, 22β-hydroxylupeol, and β-sitosterol [45][46][47][48]. According to the best of our knowledge, this is the first investigation on W. coccinea to report these bioactive phytoconstituents.…”

“…Computational docking was conducted to reveal the potential bioactivities of the identified compounds including antioxidant, cytotoxicity, antidiarrheal, hypoglycemic, and analgesic properties. To run the molecular interaction and determine the radical scavenging capacity, cytotoxicity, antidiarrheal, hypoglycemic, and central and peripheral analgesic properties, glutathione reductase (PDB ID: 3GRS), epidermal growth factor receptor (PDB ID: 1XKK), kappa opioid receptor (PDB ID: 6VI4), glucose transporter 3 [GLUT 3] (PDB ID: 4ZWB), Mu-opioid receptor (PDB ID: 5C1M), and cyclooxygenase 2 (COX-2) (PDB ID: 1CX2) proteins were selected based on the biochemical mechanisms and the current evidence [36,[42][43][44][45][46]. The targeted proteins' three-dimensional (3D) crystal structures were retrieved from the RCSB protein data bank (https://www.rcsb.org; accessed on 1 January 2022) and were saved in PDB format.…”

“…LEU 103, LEU 107, SER 136, ILE 137, TRY 140, ILE 180, TRP 183, LEU 184, SER 187, ILE 191,LEU 192 ILE 194,and VAL 195 were traced during choosing the active sites of kappa opioid receptor (PDB ID: 6VI4) to dock with the ligands for projecting antidiarrheal potentiality [43]. The active sites of the GLUT3 (PDB ID: 4ZWB), Mu-opioid receptor (PDB ID: 5C1M), and cyclooxygenase 2 (COX-2) (PDB ID: 1CX2) proteins were selected based on the literature [44][45][46]. All the 3D conformers of the ligands (SDF format) were imported into the PyRx software and were run for the energy minimization of the ligands.…”

Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

“…On the other hand, at the same concentration, 103 and 72 increase the plasma recalcification time compared to the saline group) respectively. Finally, treatment with 103 and 72 at doses of 100, 300, or 1000 μg/kg prolong the bleeding time [43].…”