Synthesis, structural analysis, and computational investigations of metronidazole and climbazole derivatives

This study details the synthesis, characterization, and in silico studies of two new molecules, 4-(3-(2-methyl-5-nitro-1H-imidazol-1-yl)propyl)phthalonitrile (5) and 1-(4-chloro-2-nitrophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutan-2-one (7), which are derivatives of metronidazole and climbazole. The structural description of nitro-climbazole (7) was confirmed by single crystal X-ray analysis, which revealed the monoclinic crystal system with the space group P2₁/n. Complementary to the experimental findings, computational studies were carried out using Density Functional Theory (DFT) with Gaussian 09 software. These calculations, including geometry optimization and frequency analysis, were performed at the mPW1PW91/6-311G(d,p) level for molecule 5 and at the wb97xd/6-311G(d,p) level for molecule 7. These analyses yielded important data regarding the stability and electronic structures of the molecules. Hirshfeld surface analysis based on CIF data obtained from the crystal structure 7 revealed intermolecular H∙∙∙H, O∙∙∙H, and Cl∙∙∙H contacts, demonstrating the contribution of these interactions to the stability of the crystal structure. Energy framework analyses elucidated the internal interactions of the structure by visualizing the cohesive forces within the crystal lattice. Frontier Molecular Orbital (FMO) analysis of molecules 5 and 7 revealed the distribution of their HOMO and LUMO orbitals, providing insights into their electronic behavior and reactivity potential. Furthermore, surface Electrostatic Potential (ESP) mapping identified electron-rich and electron-poor regions within the molecules, providing complementary information regarding potential biological interaction sites. Furthermore, their antibacterial and antifungal activities were investigated using in silico methods. This study, which combines experimental and theoretical approaches, comprehensively reveals the structural and electronic properties of the synthesized molecules.