Boroxazolidones: Synthesis, In Silico and In Vitro Evaluation as ACE/AChE Dual Inhibitors, and In Vivo Testing of Antihypertensive Activity.

BACKGROUND

Systemic arterial hypertension is a serious chronic health problem caused by multiple factors. It is a major risk factor for Cardiovascular Diseases (CVDs), including heart failure, coronary heart disease, and myocardial infarction. Hypertension can be effectively treated with inhibitors of the Angiotensin Converting Enzyme (ACE), such as captopril, enalapril, and lisinopril. However, these drugs are associated with significant adverse reactions (e.g., persistent coughing, skin rashes, and angioedema).

OBJECTIVE

Considering the recent insights obtained by our group into the antihypertensive effect of boroxazolidones, the aim of the current contribution was to design and synthesize a series of these compounds derived from α-amino acids and evaluate them (in silico and in vitro) as inhibitors of ACE and acetylcholinesterase (AChE).

METHODS

The best candidates were examined for their in vivo antihypertensive activity to regulate high blood pressure in male spontaneously hypertensive rats. Although boron-containing compounds were once thought to be toxic in any medical context, they have increasingly been used as antibiotics, antiseptics, and antineoplastic agents. BXZHis, BXZ-Lys, BXZ-Orn, BXZ-Phe, and BXZ-Pro were selected in silico as promising ACE and AChE inhibitors. After synthesis, these molecules were tested in vitro as ACE and AChE inhibitors, finding that most were effective at micromolar concentrations. The two best candidates, BXZ-Lys and BXZ-His, were evaluated in vivo with spontaneously hypertensive rats.

RESULTS

BXZ-Lys significantly decreased systolic, diastolic, and mean blood pressure, being more potent than a common ACE inhibitor, captopril.

CONCLUSION

Future research is required to elucidate the mechanism of action of this antihypertensive effect.