Substituent effects on the stability, physicochemical properties and chemical reactivity of nitroimidazole derivatives with potential antiparasitic effect: A computational study

Neglected tropical diseases caused by parasitic pathogens have caused an increase in research interest in drug discovery. Chagas disease is caused by protozoan Trypanosoma cruzi. Benznidazole and nifurtimox are effective drugs in the acute phase; nevertheless, for long-time treatment, they are toxic and have side effects, because these molecules produce free radicals and suffer oxidation–reduction processes. Studies of the structure and mode of action of these drugs have been performed and, until today, no effective treatment for this disease has been established yet. DFT-M06-2X studies in solution allowed us to explore the substituent effects on stability energy, physicochemical properties and chemical reactivity of nitroimidazoles with potential antiparasitic effects, using quantum-chemical descriptors: proton affinities, substituent effect stabilization energy, ionization potential, electrophilicity, hardness, atomic charges, dipole moment and Fukui functions. The basicity of the N3 atom and dipole moment decrease while the ionization potential, electrophilicity, and hardness increase with the electron-withdrawing substituents. Atomic charges, Fukui functions, and electrostatic potential showed that the main reactivity was on the nitro group and N3 atom. The methyl group linked to C2, and the position and inductive effect caused by the nitro group provoked major changes in the physicochemical features, chemical reactivity, and geometrical and energetic stabilities. Quantum-chemical descriptors allowed us to analyze and design novel nitroimidazole derivatives.