Synthesis, biological activity and molecular docking study of some new compounds incorporating oxygen-, nitrogen-, and sulfur- heterocycles

Abstract

In the present study, a new series of oxygen-, nitrogen-, and sulfur- heterocycles linked to benzyl moiety was designed and synthesized. So, condensation of 3-oxobutanamide 1 with malononitrile and ethyl cyanoacetate afforded the pyridinone derivative 4a & 4b. Reaction of 1 with malononitrile and sulfur element yielded thiophene derivative 8 and with arylidines 9a & 9b, 15 yielded the proposed structures 11a & 11b and 18. Further, condensation of 1 with p-aminophenol and/or hydrazine hydrate gave 22 and 23, respectively. Also, treatment of 1 with 2-amino triazole furnished triazole pyrimidinone 27. Diazotization and coupling of 1 with prepared azo compound 29 afforded the fused pyrazolone derivative 31. Finally, reaction of 1 with chalcone furnished the pyridinone derivative 36. The elucidation of structures of all synthesized compounds was confirmed by means of different spectroscopic techniques (IR, ¹H-, ¹³C-NMR, and MS). In addition, the synthesized compounds were screened for their in vitro antibacterial activities against Gram-positive bacteria, including E. casseliflavus, K. kristinae, S. haemolyticus and B. subtilis, along with Gram-negative bacteria, including E. coli. Compound 27, followed by 36 exhibited highly antibacterial activities against all bacterial strains. Moreover, molecular docking studies were performed for the synthesized compounds against E. coli FabH-CoA complex structure (PDB ID: 1hnj) to identify their binding mode of actions. The results of in silico studies are in agreement with the biological studies, as compounds 27 and 36 showed the best binding affinities (− 9.3 and − 9.0 kcal/mol) against the target, respectively. In conclusion, compounds 27 and 36 could be utilized for development antibacterial inhibitors.