Evaluation of analgesic and antiplatelet activity of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid

Abstract

Acetylsalicylic acid is used as a non-steroidal anti-inflammatory drugs (NSAID) and antiplatelet agents by inhibiting cyclooxygenases. However, therapy using acetylsalicylic acid could induce gastric bleeding and cause other gastrointestinal toxicity. The aim of this study was to demonstrate the synthesis of a new compound bearing salicylic acid residue namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid, to analyze its potential as a ligand for human cyclooxygenase-2 (COX-2) receptor, to evaluate its toxicity level and its effectiveness for analgesic and antiplatelet agent compared with acetylsalicylic acid.Synthesis of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid was conducted by microwave irradiation. The purity of this compound was evaluated with TLC, IR, NMR, and EDS spectroscopy. The chemical characterization and docking studies against human COX-2 (PDB:5F1A) was performed in-silico. The acute oral toxicity assay was performed under OECD guidelines. The analgesic activity study was performed by plantar and writhing test on animal model. For anti-platelet activity study, we performed tail-bleeding assay and flow cytometry based platelet aggregation assay. We could successfully synthesize a pure white crystalline 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid. In-Silico G-Score result of those compounds gives us preliminary hint of the potential affinity of this compound as a ligand for COX-2 receptor (PDB: 5F1A). Acute toxicity and microscopic gastrointestinal assessments indicated non-observable harmful toxicity parameters. The plantar response time of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid treated groups showed a significant increment (P < 0.01), and the nociceptive response in writhing test demonstrated a significant dose-dependent decrement. This indicated that its analgesic activity was better than acetylsalicylic acid. The platelet aggregation of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid was lower than its controls, indicating an aggregation inhibition pattern. The animals treated with 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid gave a longer bleeding time. Overall, this study demonstrated a successful synthesis of pure 2-((3-(chloromethyl)benzoyl)oxy) benzoic acid. We postulated that this compound was better than acetylsalicylic acid, exhibiting excellent analgesic and antiplatelet activity with no toxicity impact.

Characterization of Pharmacokinetics of 2-((3-(Chloromethyl)benzoyl)oxy) Benzoic Acid in Rats by Using HPLC-Dad Method

“…This phenomenon is commonly expressed by a highly lipophilic compound. This new compound, 3CBB, was reported to be more lipophilic (log P = 3.73) than ASA (log P = 1.21) as reported in our previous study [7]. The AUCtotal of 3CBB was found to be 66.3 ± 1.0 µg min/ml (table 3).…”

“…In our previous study, we investigated the analgesic, toxicity and antiplatelet effects of 3CBB. This study demonstrated that our new compound is more active and less toxic than ASA [7].…”

Anti-inflammatory activity of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid in LPS-induced rat model

“…The data indicated that 3-CH 2 Cl has a longer elimination half-life (t 1⁄2 = 39.4 ± 3.9 min) and higher C max (0.57 ± 0.02 μg/mL) compared to ASA. These pharmacokinetic parameters showed that 3-CH 2 Cl is widely and deeply distributed in all body tissues, yielding a slower onset of action and longer elimination time compared to ASA [9]. Moreover, our studies on in vitro human platelet aggregation studies postulated the mechanism of antiplatelet activity of 3-CH 2 Cl, by inhibiting COX-1.…”

“…Our group recently synthesized a new compound derived from salicylic acid, namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3-CH 2 Cl) that has the benefits of acetylsalicylic acid but lacks its harmful side effects [9]. The analgesic and anti-platelet activity of 3-CH 2 Cl wa s administered in normal Wistar rats.…”

“…Moreover, our studies on in vitro human platelet aggregation studies postulated the mechanism of antiplatelet activity of 3-CH 2 Cl, by inhibiting COX-1. Furthermore, in silico studies demonstrated a better af finity of 3-CH 2 Cl for the COX2 receptor (PDB : 5F1A) than ASA [9]. Indeed, the COX-2 protein is predominantly induced by the main sources of prostaglandins (PGs) during inflammation [8].…”