Premium
Evaluation of Phthalamide derivatives as ACE/AChE/BuChE inhibitors against cardiac hypertrophy produced by Hypertension
Author(s) -
Rodriguez Jessica,
LagosCruz Jesús A.,
RojasJiménez Josué I.,
EstradaSoto Samuel E.,
GallardoOrtíz Itzell A.,
TrujilloFerrara José G.,
VillalobosMolina Rafael,
AndradeJorge Erik
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02993
Subject(s) - captopril , muscle hypertrophy , medicine , blood pressure , in vivo , pressure overload , cardiac function curve , in silico , heart failure , pharmacology , endocrinology , cardiology , cardiac hypertrophy , biology , biochemistry , microbiology and biotechnology , gene
Cardiac hypertrophy is a major adaptative response to the increase in the overload produced by hypertension, it is a risk factor for myocardial infarction, stroke, and heart failure. Among the several factors involved in hypertension and in the progression to cardiac hypertrophy, the hyperactivity of the renin‐angiotensin system (RAS) and the dysfunction of the neurovisceral/autonomic nervous system are the main mechanisms involved. Evidence demonstrate that the inhibition of RAS and the increase in parasympathetic activity ameliorate cardiac function and reduce significantly cardiac hypertrophy. Thus, this study aimedto evaluate molecules as three‐target inhibitors (ACE/AChE/BuChE) with the possible dual effect on blood pressure and cardiac remodeling. Three phtalamide derivatives (M‐01, M‐02, and M‐03) were evaluated in silico , in vitro and in vivo experiments. Results All three phthalamide derivatives showed in silico and in vitro good competitive inhibition on the three target enzymes. M‐01 (10 mg/kg) significantly reversed cardiomyocite hypertrophy (by 87.3%, p<0.001) in the heart of 20 week‐old spontaneously hypertensive rats, being at least 18‐fold more potent than the reference drug (captopril), which provided only 32.7% reversion. Conclusion Three‐target inhibitory activity was herein demonstrated for M‐01, M‐02, and M‐03 in vitro and in silico , each with a similar effect. The compound tested in vivo (M‐01) exhibited great potency in reducing blood pressure and reverting cardiomyocyte hypertrophy, making it a promising candidate for further research.