背景:系统性动脉高血压是由多种因素引起的严重慢性健康问题。它是心血管疾病(CVDs)的主要危险因素,包括心力衰竭,冠心病,和心肌梗塞。血管紧张素转换酶(ACE)抑制剂可以有效治疗高血压,比如卡托普利,依那普利,还有赖诺普利.然而,这些药物与显著的不良反应相关(例如,持续咳嗽,皮疹,和血管性水肿)。
目的:考虑到我们小组对硼恶唑酮的抗高血压作用的最新见解,当前贡献的目的是设计和合成一系列源自α-氨基酸的这些化合物,并评估它们(计算机和体外)作为ACE和乙酰胆碱酯酶(AChE)的抑制剂。
方法:在雄性自发性高血压大鼠中检查最佳候选者的体内抗高血压活性以调节高血压。尽管含硼化合物曾经被认为在任何医学背景下都是有毒的,它们越来越多地被用作抗生素,防腐剂,和抗肿瘤药.BXZHis,BXZ-Lys,BXZ-Orn,BXZ-Phe,和BXZ-Pro被选择为有前途的ACE和AChE抑制剂。合成后,这些分子作为ACE和AChE抑制剂在体外进行了测试,发现大多数在微摩尔浓度下有效。两个最好的候选人,BXZ-Lys和BXZ-His,用自发性高血压大鼠进行体内评估。
结果:BXZ-Lys收缩压显著降低,舒张压,和平均血压,比常见的ACE抑制剂更有效,卡托普利.
结论:需要进一步的研究来阐明这种抗高血压作用的作用机制。
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.
CONCLUSIONS: Future research is required to elucidate the mechanism of action of this antihypertensive effect.