Origanum vulgare L.: In vitro Assessment of Cytotoxicity, Molecular Docking Studies, Antioxidant and Anti-inflammatory Activity in LPS Stimulated RAW 264.7 Cells.

BACKGROUND: Inflammation involves a dynamic network that is highly regulated by signals that initiate the inflammation process as well as signals that downregulate it. However, an imbalance between the two leads to tissue damage. Throughout the world, inflammatory disease becomes common in the aging society. The drugs which are used clinically have serious side effects. Natural products or compounds derived from natural products show diversity in structure and play an important role in drug discovery and development. OBJECTIVE: Oreganum Vulgare is used in traditional medicine for various ailments including respiratory and rheumatic disorders, severe cold, suppression of tumors. The current study aims to evaluate the anti-inflammatory potential by evaluating various in vitro parameters. METHODS: Inflammation-induced in macrophages via LPS is the most accepted model for evaluating the antiinflammatory activity of various plant extracts and lead compounds. RESULTS: The extracts (OVEE, OVEAF) as well as the isolated compound(OVRA)of Oreganum Vulgare inhibit the pro-inflammatory cytokines (IL-6 and TNF-α) and NO without affecting cell viability. CONCLUSION: Our study established that the leaf extracts of Oreganum vulgare L. exhibit anti-inflammatory activity and thus confirm its importance in traditional medicine.

Preclinical comprehensive physicochemical and pharmacokinetic profiling of novel nitroimidazole derivative IIIM-019 - A potential oral treatment for tuberculosis.

New compounds against tuberculosis are urgently needed to combat the crisis of drug resistance in tuberculosis (TB). We have identified a nitrodihydroimidazooxazole analog, IIIM-019 as a new anti-tubercular agent with a MIC of 0.23 µM against H37Rv. Physicochemical properties, in-vitro pharmacokinetics and in-vivo multiple-doses pharmacokinetics were studied for the compound. In silico physicochemical parameters and Lipinski's violations were determined for drug like properties. Lipophilicity was determined experimentally as Octanol-PBS partition coefficient (log P). Passive and active permeability of the compound was determined by PAMPA and Caco-2 cell permeability analysis, respectively. Plasma protein binding was determined by Rapid equilibrium dialysis. Metabolism by liver microsomes revealed the t1/2 and intrinsic clearance of the compound. Hepatotoxicity of IIIM-019 was determined alone and in combination to first line anti-tubercular drugs. The compound was also estimated for nuclear DNA damage. Single doses of IIIM-019 (2.5, 10, 25 and 100 mg/kg) were administered orally to Balb/c mice and the blood samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). IIIM-019 exhibited very good lipophilicity (log P) of 2.47 which makes it optimal for oral administration. The compound showed low solubility and permeability and high plasma protein binding. However, it was highly stable in rat liver microsomes with t1/2 > 2 h and very low intrinsic clearance. It was found to be non-hepatotoxic and did not induce any significant DNA damage at high concentrations even up to 100 µM. IIIM-019 showed satisfactory in-vivo pharmacokinetic properties. By increasing the dose from 2.5 mg/kg to 10 mg/kg, AUC0-t increased from 14935 ng h/ml to 81,478 ng h/ml. However the exposure of IIIM-019 in plasma suggested that the levels reached saturation at higher concentrations. The compound showed a good oral bioavailability of 58.7%. The results insinuate that IIIM-019 should undergo further development as a potential treatment for tuberculosis.