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

Tauqeer Ahmed,Arif-ullah Khan,Aslam Khan,Muzaffar Abbass,Edson Rodrigues Filho,Zia Ud Din

doi:10.1186/s13065-018-0507-1

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.

Highlights

Pain is an unfavorable sensory and emotional experience that is associated with the potential tissue damage and explained in terms of such damage [1]
Calcium chloride (CaCl2), diclofenac sodium, heparin, phosphate buffers solution (PBS) and sodium citrate were obtained from Sigma chemicals., Dt
The results of E-values, hydrogen bonds and binding residues of AK-1a and AK-2a with target proteins involved in platelet aggregation along with standard drugs are shown in Table 2 and Figs. 7, 8, 9

Summary

Introduction

Pain is an unfavorable sensory and emotional experience that is associated with the potential tissue damage and explained in terms of such damage [1]. Noxious effects such as ulceration, gastrointestinal bleeding by non-steroidal anti-inflammatory drugs and drowsiness, nausea and tolerance by opiates usage limits their use in management of pain [2]. Coagulation cascade involves intrinsic and extrinsic pathways [7] The former has a role in the growth and maintenance of fibrin while the later plays its role in the initiation of fibrin formation. Dibenzylidene ketone derivatives contain a dienone system connecting two aryl groups at the ends of a C 5 carbon chain. AK-1a and AK-2a were investigated for their analgesic, antiplatelet and anticoagulant effects using different pharmacological and computational assays

Methods

Results

Discussion

Conclusion