Síntese e avaliação de derivados de fenois naturais como agentes inibidores da enzima conversora de angiotensina

Abstract

Hypertension is a chronic disease that affects people all over the world. It can lead to various complications for the patients and even death. An important class of antihypertensive drugs are the angiotensin converting enzyme inhibitors (ACEI), which in addition to lowering blood pressure levels by inhibiting the formation of a potent vasoconstrictor agent (Angiotensin II), helps in other pathologies such as heart failure and diabetic nephropathy. Despite these facts, the ACE inhibitors adverse effects may cause the adherence to treatment to be impaired. Hence, the search for new representatives of this class, especially of natural origin, is a needed and important strategy for discovering superior drugs. Studies have reported that some phenolic derivatives of natural products have an inhibitory activity against ACE, such as eugenol, eugenol glycosides and vanillin glycosides. Therefore, it was aimed to obtain eighteen derivatives of these substances to assess their activity profiles as a function of the made structural modifications. The proposed substances were successfully obtained from classical reactions of O-methylation, O-benzylation, O-glycosylation, oxidation and reduction. All obtained compounds were characterized by infrared (IR) and nuclear magnetic resonance spectroscopy (NMR). Subsequently, the substances were subjected to in vitro screening, at the fixed concentration of 2 mmol.L-¹. The most active substances, capable of inhibiting at least 60% of ACE activity, had their IC50 values determined, being them FN01 (IC50 1.7 ± 0.3 mmol.L-¹), FNG01 (IC50 1.0 ± 0.15 mmol.L-¹), FN02 (IC50 1.3 ± 0.3 mmol.L-¹), FNG02 (IC50 1.1 ± 0.2 mmol.L-¹), FNG03 (IC50 1.0 ± 0.2 mmol.L-¹) and FNG05 (IC50 1.8 ± 0.2 mmol.L-¹). These results demonstrate that the presence of hydrophilic substituents helps the interaction of the substances with the ACE binding site, whereas hydrophobic groups on the phenolic hydroxyl substituent, negatively impacting the inhibitory potential. Molecular modeling studies are being conducted to evaluate the interaction between each of these best derivatives and ACE. In this way, these substances can serve as prototypes for structural optimization and future investigations as potential ACEI agents.