Synthesis, in vitro and in silico Studies of Alkylated Paracetamol Derivatives as Potential Antibacterial Agent

Abstract

In the field of drug development, structural modification of over-the-counter drugs is extensive to combat drug-resistant strains as well as discover new purposes or biological applications. Paracetamol is an example of OTC analgesic drug that is commonly used in the treatment of pain and fever. In this research, paracetamol was modified by introducing various alkyl chains CnH2n+1, where n varied from 3 to 14 via Williamson etherification with bromoalkanes to yield 49% – 86% of N-(4-oxy)phenyl)acetamide derivatives 1-10. Employing the Kirby-Bauer disc diffusion method, the bacteriostatic activity of the series in comparison to the parental compound (paracetamol) and standard drug (ampicillin) showed that compounds 1 (n = 3), 4 (n = 6) and 7 (n = 9) displayed excellent activity against Escherichia coli with an inhibition zone of 8.1 ± 0.4 mm, 8.3 ± 0.4 mm and 7.9 ± 0.5 mm, respectively, while the paracetamol and ampicillin inhibition zones are 8.0 ± 0.0 mm and 16.0 ± 0.0 mm, respectively. Interestingly, compounds 7 (n = 9) and 10 (n = 14) exhibited excellent activity towards Staphylococcus aureus with an inhibition zone of 8.2 ± 0.4 mm and 12.5 ± 0.5 mm, respectively, outperforming paracetamol (6.0 ± 0.0 mm) and ampicillin (11.0 ± 0.0 mm). The in vitro findings were in line with the molecular docking investigation conducted using AutoDock Vina software towards the active site of DNA gyrase enzymes, revealing the structure-activity relationship of the series. Besides, the synthesised compounds 1-10 complied with the drug-likeness analysis and ADME pharmacokinetics profile. The results of this study are significant in delivering new prospects of the potential antibacterial drugs obtained through derivatisation of the known drug, paracetamol. While these initial results are promising, further toxicity and in vivo analyses are necessary to ensure the efficacy and safety of the newly developed drug in living organisms, providing a clearer understanding of its potential as an antibacterial medicine.