TY - JOUR
T1 - Phthalamide derivatives as ACE/AChE/BuChE inhibitors against cardiac hypertrophy
T2 - an in silico, in vitro, and in vivo modeling approach
AU - Andrade-Jorge, Erik
AU - Rodríguez, Jessica E.
AU - Lagos-Cruz, Jesús A.
AU - Rojas-Jiménez, Josué I.
AU - Estrada-Soto, Samuel E.
AU - Gallardo-Ortíz, Itzell A.
AU - Trujillo-Ferrara, José G.
AU - Villalobos-Molina, Rafael
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
PY - 2021/4
Y1 - 2021/4
N2 - Left ventricular hypertrophy (LVH) is a major adaptative response to the increase in the overload produced by hypertension, 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 demonstrates that the inhibition of RAS and the increase in parasympathetic activity reduce significantly LVH ameliorating cardiac function. The development of multi-target compounds is a relevant strategy for treating hypertension and cardiac hypertrophy. This study aimed to synthesize three phthalamide derivatives (M-01, M-02, and M-03) and evaluate them as three-target (ACE/AChE/BuChE) inhibitors with the possible dual effect of reducing hypertension and reverting cardiac hypertrophy. After in silico and in vitro experiments, one compound was tested in vivo on rats. All three phthalamides were synthesized in good yields, showing good competitive inhibition of the three-target enzymes in silico and in vitro. M-01 (10 mg/kg) significantly reversed cardiomyocite hypertrophy (by 87.3%; p < 0.001) in the heart of spontaneous hypertensive rat (SHR) model. It was at least 18-fold more potent than the reference drug (captopril), which provided only 32.7% reversion. 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 hypertension and reverting cardiomyocyte hypertrophy, making it a promising candidate for further research. [Figure not available: see fulltext.]
AB - Left ventricular hypertrophy (LVH) is a major adaptative response to the increase in the overload produced by hypertension, 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 demonstrates that the inhibition of RAS and the increase in parasympathetic activity reduce significantly LVH ameliorating cardiac function. The development of multi-target compounds is a relevant strategy for treating hypertension and cardiac hypertrophy. This study aimed to synthesize three phthalamide derivatives (M-01, M-02, and M-03) and evaluate them as three-target (ACE/AChE/BuChE) inhibitors with the possible dual effect of reducing hypertension and reverting cardiac hypertrophy. After in silico and in vitro experiments, one compound was tested in vivo on rats. All three phthalamides were synthesized in good yields, showing good competitive inhibition of the three-target enzymes in silico and in vitro. M-01 (10 mg/kg) significantly reversed cardiomyocite hypertrophy (by 87.3%; p < 0.001) in the heart of spontaneous hypertensive rat (SHR) model. It was at least 18-fold more potent than the reference drug (captopril), which provided only 32.7% reversion. 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 hypertension and reverting cardiomyocyte hypertrophy, making it a promising candidate for further research. [Figure not available: see fulltext.]
KW - ACE inhibitor
KW - AChE inhibitor
KW - BuChE inhibitor
KW - Cardiac hypertrophy reversion
KW - Hypertension
KW - Molecular docking
UR - http://www.scopus.com/inward/record.url?scp=85100489987&partnerID=8YFLogxK
U2 - 10.1007/s00044-021-02707-8
DO - 10.1007/s00044-021-02707-8
M3 - Artículo
AN - SCOPUS:85100489987
SN - 1054-2523
VL - 30
SP - 964
EP - 976
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
IS - 4
ER -