Estudo de ancoragem molecular de derivados de ácido cinâmico frente à enzimas do ciclo replicativo do HIV-1

Abstract

The infection caused by HIV is a global public health problem, demonstrating the necessity to research for new and more effective drugs with fewer side effects. Thus, looking for to contribute to advances in the treatment of infections caused by HIV, the present work aimed to perform in silico studies to evaluate the potential antiretroviral esters and amides derivatives of cinnamic acid, as well as a proposal for the synthesis thereof. For this, 25 compounds synthesized from esterification reactions with cinnamic acid have been proposed, evaluated their ADMET properties and molecular docking study with reverse transcriptase and HIV-1 protease enzymes. Also, it was synthesized and characterized five of the compounds evaluated in silico studies, guaiacol, 3-acetophenone, vanillin, eugenol, and the thymyl cinnamates. With the assessment of the ADMET properties, it was observed that the evaluated compounds have favorable properties to a good oral bioavailability and significantly lower toxicological effects than those present in the derivation of the protagonists. The results also indicate that a few compounds inhibit some cytochrome enzymes, which is a significant disadvantage found in the evaluated compounds. Although the studies performed with reverse transcriptase enzyme shown better interaction energy values, the compounds did not interact in a favorable region to inhibit the enzyme. However, studies with protease enzymes presented a lower interaction energy. Also, studies with the proteases were favored by the region where all ligands showed lower interaction energy, inside the allosteric site. With favorable interactions in energy and location, the molecular docking studies indicated a greater potential to inhibit the protease enzyme, it is the enzyme-ligand interaction region the main reason for this conclusion. Synthesis of guaiacol, 3-acetophenone, vanillin, eugenol, and thymyl cinnamates occurred successfully obtaining an average yield of 60%. The synthesized compounds were characterized by 1H and 13C NMR, showed chemical shifts consistent with literature data, enabling to establish the complete assignment of the chemical shift of hydrogen and carbon-13.