Phytochemical screening and preliminary clinical trials of the aqueous extract mixture of Andrographis paniculata (Burm. f.) Wall. ex Nees and Syzygium polyanthum (Wight.) Walp leaves in metformin treated patients with type 2 diabetes

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.

Introduction: Salicylic acid derivate is very popular for its activity to suppress pain, fever, and inflam ma tion. One of its derivatives is acetylsalicylic acid (ASA) wh ich has be en reported repeatedly that, as a nonsteroidal anti-inflam ma tory drug (NSAID), it has a cardioprotective effect. Although ASA has various advantages, several stud ies have reported that it ma y indu ce severe peptic ulcer disease. We recently synthesized a new compoun d derived from salicylic acid, name ly 2-((3-(chloromethyl)be nz oyl)oxy)be nz oic acid (3 -CH 2 Cl) wh ich still has the be nefit of acetylsalicylic acid as an analgesic and antiplatelet, bu t lacks its harmful side effects (Caroline et al., 20 19 ). In addition, in silico stud ies of 3-CH 2 Cl showed a higher affinity towards protein receptor cyclooxygenase-2 (COX-2; PDB: 5F1A ) than ASA. We hypothesized that 3-CH 2 Cl inhibits the COX-2 activity wh ich could presumably decrease the inflam ma tory responses. However, no knowledge is available on the anti-inflam ma tory response and molecular signaling of this new compoun d. Henc e, in this stud y, we investigated the potential func tional relevanc e of 3-CH 2 Cl in regulating the inflamma tory response in lipopolysacch aride (LPS)-indu ced rats. The results of this stud y show that this compoun d could significantly redu ce the inflam ma tory parame ter in LPS-indu ced rats. Material and methods: Rats were indu ced with LPS of 0.5 mg/kg bw intravenously, prior oral administration with vehicle (3 % Pulvi s Gumm i Arabicum / PGA), 50 0 mg/60 kg body weight (b w; rat dosage converted to hu ma n) of 3-CH 2 Cl and ASA. The inflam ma tory parame ters such as ch anges in the temperature of septic shock, cardiac blood plasma concentrations of IL-1β and TNF-α (ELISA), blood inflam ma tion parame ters, wh ite blood cell concentrations, and lung histopathology were observed. Meanwh ile, the stability of 3-CH 2 Cl powder was evaluated. Result: After the administration of 50 0 mg/60 kg bw of 3-CH 2 Cl (rat dosage converted to hu ma n) to LPSindu ced rats, we observed a significant redu ction of both TNF-α (5 .70+ /-1.04 × 10 3 pg/mL, p= <0 .001 ) and IL-1β (2 .32+ /-0.28 × 10 3 pg/mL, p= <0 .001 ) cardiac blood plasma concentrations. Besides, we foun d a redu ction of wh ite blood cell concentration and the severity of lung injury in the 3-CH 2 Cl group compared to the LPS-indu ced rat group. Ad ditionally, this compoun d ma intained the rat body temperature within norma l limits du ring inflam ma tion, preventing the rats to un dergo septic shock, ch aracterized by hypothermic (t = 12 0 min.) or hyperthermic (t = 36 0 min) conditions. Furthermore, 3-CH 2 Cl was foun d to be stable un til 3 years at 25°C with a relative hu midity of 75 ± 5% . Conclusion: 3-CH 2 Cl compoun d inhibited inflam ma tion in the LPS-indu ced inflam ma tion response model in rats, hypothetically through bind ing to COX-2, and presumably inhibited LPS-indu ced NF-κβ signaling pathways. This stud y could be used as a preliminary hint to investigate the t...

Objective: A new compound of salicylic acid derivative, namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3CBB), was synthesized to find a compound exhibiting higher analgesic activity and smaller ulcer irritation than acetylsalicylic acid (ASA). Therefore, this study aimed to investigate the pharmacokinetics of this new compound in rats, following a single dose oral administration of 3CBB (45 mg/kg BW). Methods: Plasma samples of 9 healthy rats were collected before and up to 3 h after its oral administration, following an 18 h fasting period. Plasma concentrations of 3CBB were determined using a validated HPLC-DAD assay. Pharmacokinetic parameters were determined using the compartment model technique. All experiments were carried out in triplicate. Results: The pharmacokinetic parameters of 3CBB obtained were as follows: Tmax= 28.9±1.1 min, Cmax = 0.57±0.02 µg/ml, AUCtotal = 66.3±1.0 µg min/ml, Kel = 0.018±0.002 min-1, and T1/2el = 39.4±3.9 min. The long elimination half-life and low Cmax indicated that 3CBB was extensively distributed in the deep and very deep tissues. This confirmed the unique and special characteristics of a highly lipophilic compound like 3CBB (log P = 3.73). Conclusion: 3CBB demonstrated a slower onset of action and longer elimination time from the body compared to ASA. Thus this new compound is a potential candidate to be developed as a new drug.

Purpose: This research determines the effect of sodium lauryl sulfate (SLS) as a surfactant, croscarmellose sodium (CS) as a disintegrating agent, and SLS–CS combinations on 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3CH 2 Cl) (log P = 3.73) tablet formulations. In addition, this study aims to determine the optimum of the 3CH 2 Cl tablet formula. Methods: The tablets are manufactured through direct compression according to the simplex lattice design. The optimal SLS and CS concentration was determined in vitro using linear and quadratic models to achieve better tablet disintegration and dissolution. Results: The same linear and quadratic coefficient profiles of SLS and CS indicate that the combined coefficient of SLS–CS with a quadratic model can be used to predict the effect of the SLS–CS combination. Based on the linear model coefficients, SLS and CS increase the value of flow time (9.35; 7.65), Carr index (26.17; 21.17), hardness (9.84; 7.44), friability (0.38; 0.31), disintegrating time (5.74; 2.62), and drug release (84.28; 58.65). The quadratic model coefficient shows that SLS–CS combinations increase flow time (0.60), Carr index (2.00), hardness (1.00), and disintegrating time (1.04). Meanwhile, they decrease friability (−0.02) and drug release (−9.10). Conclusions: SLS, CS, and SLS–CS combinations affect the quality of tablet mass and tablets. The optimum tablet formula was 3CH 2 Cl (300 mg), Ne (9.38%), SLS (0.92%), CS (2.33%), MCC (5%), and SDL (ad 800 mg). 3CH 2 Cl has analgesic activity despite the presence of tablet excipients. The 3CH 2 Cl tablet is an innovative formulation and a new alternative for future analgesic drugs.