Synthesis, Antimicrobial Activities and Molecular Docking Studies of New N-Acylated Derivatives of 5-(2-Phenyl-1,8-naphthyridin-3-yl)-1,3,4-oxadiazol-2-amine

Abstract

Present study establishes a novel synthetic route of N-acetylated derivatives of 5-(2-phenyl-1,8-naphthyridine-3-yl)-1,3,4-oxadiazole-2-amine (6a-j), which was achieved in four steps with good yields. 2-Amino nicotinaldehyde and ethyl 3-oxo-3-phenylpropanoate on refluxing with triethylamine in ethanol undergoes Friedlander synthesis to furnish ethyl 2-phenyl-1,8-naphthyridine-3-carboxylate, which further converted into 2-phenyl-1,8-naphthyridine-3-carbohydrazide by reacting with hydrazine hydrate upon reflux, followed by cyclization with cyanogen bromide in the presence of water and 1,4-dioxane with sodium bicarbonate to afford 5-(2-phenyl-1,8-naphthyridin-3-yl)-1,3,4-oxadiazol-2-amine (5). Compound 5 was acetylated using numerous symmetrical anhydrides to synthesize novel N-acetylated derivatives (6a-j). The IR, 1H, 13C NMR and mass spectral analysis were used to characterize the structure of synthetic compounds. The synthesized compounds were evaluated for their antimicrobial efficiency against bacteria (S. aureus and E. coli) using ampicillin as a standard reference and against fungi (C. albicans) using fluconazole as a standard reference. Compound 6e exhibited good antibacterial properties while compounds 6c and 6e had shown high antifungal activity, whereas remaining compounds shown moderate to weaker antimicrobial activity. The synthesized derivatives verified their docking strength against Mtb MurB (PDB ID: 5JZX) and showed significant docking activity, however, compound 6f (-10.98 kcal/mol) and compound 6b (-10.52 kcal/mol) had a strong binding affinity compared to the other synthesized compounds.