Metronidazole Cinnamate: Synthesis, Characterization and Antimicrobial Potential Evaluation

Abstract

Imidazole and its derivatives, especially nitroimidazoles can be derivatized to improve the pharmacokinetic parameters and solubility issues of the poorly soluble pharmacological entities. The present study aimed at two-pot synthesis of ester of metronidazole with cinnamic acid through esterification reaction. Thin layer chromatography (TLC) and melting point determination techniques were used to determine the purity of synthesized ester. For the structural elucidation, spectral techniques like FTIR and NMR were performed. In silica studies of the synthesized ester were carried out using different software and online web tool. Pharmacokinetic parameters including ADME (absorption, distribution, metabolism and toxicity), drug likeness and ligand-receptor binding interaction were assessed in silica using Mol Soft, SwissADME, Swiss Target Prediction and docking. In vitro assays including antioxidant, anti-microbial, enzyme inhibition, cytotoxicity, antifungal and hemolytic assay were accomplished to appraise the biological potential of metronidazole cinnamate. A comparative analysis was made between the in vitro biological activities of metronidazole (US-O 1), cinnamic acid (US-02), metronidazole cinnamate (US-03) and mixture of equimolar concentration of (US-OI, US-02 & US-03) designated as (US-04) to evaluate the difference in pharmacological potential by the virtue of functional group modification. In silica analysis showed that metronidazole cinnamate complies with the Lipinski's rule of five and is lead like as it has shown the drug likeness score ofO.SO. Significant oral absorption was predicted by boiled egg method whereas, 10gP value of 2.22 indicated its lipophilic character. A proficient binding interaction was shown by US 03 with epidermal growth factor receptor (binding energy -7.4 Kcallmol) and protein tyrosine kinase (binding energy -7.0 Kcallmol) The results indicate that a significant antioxidant potential was manifested by metronidazole cinnamate (US-03) in terms of total antioxidant capacity (lS.l1S±0.048 Ilg AAE/mg of sample) and total reducing power of (43.2S±0.04I Ilg AAE/mg of sample). Likewise, the highest antioxidant potential was observed in US 04 as total antioxidant capacity (28.323±0.034 Ilg AAE/mg of sample) and total vii reducing power of (51.15±0.021 Ilg AAE/mg of sample). US-03 has exhibited the most potent antibacterial activity against non-resistant E. coli (MIC = 50 Ilg/ml), P. aeruginosa (MIC = 25 Ilg/ml), B. subtilis (MIC = 25 Ilg/ml) and Methicillin resistant Staphylococcus aureus MRSA (MIC = 50 Ilg/ml). Significant inhibition in a-amylase activity was shown by US-03 (26.50±0.15%) and recorded maximum in US-04 (40±0.16%). No significant protein kinase inhibition and urease inhibition activity was observed, whereas, in cytotoxicity assay, US-04 has shown the greatest percentage mortality with LCso 6.299 Ilg/ml. Principally, the results of undertaken study proposed that ester (metronidazole cinnamate) is a potential candidate as antioxidant, antimicrobial, enzyme inhibitor and cytotoxic. Therefore, further preclinical studies are recommended to collaborate the in vitro and in silico findings.