Anti-inflammatory and analgesic potential of newly synthesized 2,3-disubstituted thiazolidine-4-one derivatives: Insights from molecular simulation and in vivo studies

Abstract

Inflammation is the central pathway of various pathological condition occurring as a result of injury or infection and severely affects quality of life. It is well documented that cyclooxygenase 2 (COX-2) signaling plays a significant role in potentiating inflammation. In the current study, two 2,3-disubstituted thiazolidine-4-one derivatives, (E)-3-benzyl-2-((Z)-(1-(4-bromophenyl)ethylidene)hydrazono)thiazolidin-4-one (BEHT) and (E)-2-((Z)-(1-(4-chlorophenyl)ethylidene)hydrazono)-3-(4-nitrobenzoyl)thiazolidin-4-one (CEHNT) were synthesized and their anti-inflammatory, anti-oxidant and analgesic potential were investigated. The synthesized compounds were spectroscopically analyzed by infrared (IR) spectroscopy, nuclear magnetic resonance (1H NMR, and 13C NMR). Preliminary total anti-oxidant capacity (TAC), total reducing power (TRP), and free radical scavenging potential were evaluated. In vitro COX-2 inhibitory effect of both compounds were also investigated. Subsequently, acute and sub-acute toxicity of BEHT and CEHNT were investigated. Next, acute analgesic and anti-inflammatory activities which include hot plate test, acetic acid induced writhing behavior, formalin induced paw licking test, and carrageenan induced inflammation model were established. Additionally, molecular docking and simulation were carried out to interpret the variable inhibitory activity of BEHT and CEHNT against COX-2 signaling. The in vitro findings demonstrate promising anti-oxidant, free radical scavenging and COX-2 inhibitory potential of synthesized derivatives. Both compounds show no signs of acute (1000 mg/kg) or subacute toxicity (500 mg/kg) in mice based on histopathology, body weight, and serum biomarkers. Moreover, the compounds exhibit strong anti-inflammatory and analgesic potential in acetic acid-induced writhing behavior, heat-induced hypersensitivity, formalin-induced paw licking test, and carrageenan-induced inflammation model. The molecular docking (MD) and simulation results claimed that BEHT and CEHNT possess strong binding affinities and interaction towards COX-2, demonstrating the mechanism for their anti-inflammatory and analgesic activities. The current findings indicate that BEHT or CEHNT exert marked anti-inflammatory and analgesic activities.