Hydrazone-bridged 5-nitrofuran and piperidine/piperazine derivatives: Synthesis, DFT studies, and evaluation of anticancer and antimicrobial activity

In the present study, we designed eleven novel compounds (PNH1-PNH11) by combining three pharmacophores, namely piperidine/piperazine, 5-nitrofuran, and hydrazone, that were frequently reported in the chemical structures of antimicrobial and anticancer agents. The target compounds were obtained by reacting 5-nitrofuran-2-carbaldehyde and in-house synthesized hydrazide derivatives carrying piperidine/piperazine moiety. After confirming the proposed structures by various spectral techniques, PNH1-PNH11 were tested for their anticancer and antimicrobial activities. Based on the biological data obtained, PNH4 ((E)-4-(4-(4-methoxyphenyl)piperazin-1-yl)-N'-((5-nitrofuran-2-yl)methylene)benzohydrazide) appeared to be the most attractive derivative in this series as an effective cytotoxic agent with concurrent antibacterial activity. Molecular docking studies within nitroreductase were applied to support the antibacterial activity mechanism of PNH4 and to explain its superior activity compared to the other synthesized compounds. Furthermore, natural bond orbital (NBO) analysis, potential energy surface (PES) scanning investigations, HOMO-LUMO energies, and molecular electrostatic potential (MEP) and contour maps calculations were carried out to gain insights into the structural properties, chemical reactivity, and stability of the most active compound using density functional theory (DFT) at the B3LYP functional using basis set 6–31G(d,p).