Phthalamide derivatives as ACE/AChE/BuChE inhibitors against cardiac hypertrophy: an in silico, in vitro, and in vivo modeling approach

Abstract

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.

Highlights

  • The phthalamide derivatives are three-target inhibitors, acting on ACE, AChE, and BuChE.

  • The test compounds showed potency in treating hypertension and reverting cardiomyocyte hypertrophy.

  • M-01 was 18-fold more potent than captopril in reversing cardiomyocyte hypertrophy.

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Acknowledgements

EAJ received a postdoctoral fellowship from DGAPA of the Universidad Nacional Autónoma de México (UNAM). Additionally, this work was supported by CONACYT-México, SIP-projects (M1930, and 20201031) from the Instituto Politécnico Nacional-ESM, and RVM and IAGO received grants from PAPIIT (IN223519 and IN226819, respectively). We thank MVZ L. Flores, MD. F. Barrón-Moreno, C.Y. Gallegos-Quiroz, and Biol. TE Villamar-Duque from Facultad de Estudios Superiores Iztacala (FESI), UNAM, for their aid in animal care and housing.

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Andrade-Jorge, E., Rodríguez, J.E., Lagos-Cruz, J.A. et al. Phthalamide derivatives as ACE/AChE/BuChE inhibitors against cardiac hypertrophy: an in silico, in vitro, and in vivo modeling approach. Med Chem Res (2021). https://doi.org/10.1007/s00044-021-02707-8

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Keywords

  • Hypertension
  • Molecular docking
  • ACE inhibitor
  • AChE inhibitor
  • BuChE inhibitor
  • Cardiac hypertrophy reversion