Planejamento e desenvolvimento de análogos da nitazoxanida

Abstract

Nitazoxanide is a molecule applied in the antihelminthic therapy and has a broad spectrum as antiparasitic agent. In biological studies by using this molecule, new therapeutic targets and good results were found. Nevertheless, it still has some chemical and pharmaceuticals problems which need improvements. The objective of the study is the design and development of stable nitazoxanide derivatives using molecular modeling and organic synthesis approaches. All calculations of electronic properties such as frontier orbital (HOMO and LUMO), ionization potential (IP) and electronic affinity (AE), electrostatic potential map (MPE) were performed using the Gaussview e Gaussian. The theoretical study of nine amino-nitro-azolic derivatives, an essential moiety of nitazoxanide pharmacophore, was performed using the DFT/B3LYP/6-31G (d,p) method and showed that thiophene ring modifications can reduce the redox potential changing the reactivity and toxicity. All derivatives have better electrophilic properties and depends on the presence of nitro group. These results are confirmed by maps of electrostatic potentials and can indicated the most reactive regions that probable act on electrophilic attacks. Physicochemical parameters of nitazoxanide analogues were also evaluated using the DFT/B3LYP/6-31+G (d,p) method. A significant increase in the electron donating capacity for these new molecules from the HOMO, LUMO and GAP values was observed. An additional nitro group on ring structure beget compounds that have great stability and electron-accepting capacity. This electronic property is essential for biological activity on nitro compounds. The electrostatic potentials for nitazoxanide and its related analogues show the significant negative charge density on the nitro region. In addition, a conformational analysis of nitazoxanide, tizoxanide and a nitazoxamide derivatives was performed. The lower conformer of nitazoxanide agrees with the crystallographic structure. The more stable structures of the derivatives are related to their conformational similarity. The nitazoxanide molecule and three other derivatives have been synthesized and are available for biological evaluation on future works.