Medicinal Chemistry Research

, Volume 28, Issue 5, pp 681–695 | Cite as

Novel phthalamide derivatives as antihypertensive agents: rapid and clean synthesis, in silico and in vivo evaluation

  • Erik Andrade-Jorge
  • Jessica E. Rodríguez
  • José Bribiesca-Carlos
  • Itzell A. Gallardo-Ortíz
  • José G. Trujillo-FerraraEmail author
  • Rafael Villalobos-MolinaEmail author
Original Research


Hypertension is a prevalent progressive disorder and a key risk factor for cardiovascular disease, stroke, and kidney disease. Angiotensin-I-converting enzyme (ACE) inhibitors are the first-line drugs for treating hypertension, but they have many side effects. ACE is a zinc dipeptidyl carboxypeptidase that cleaves the decapeptide angiotensin-I to form the vasopressor angiotensin-II. Since the latter molecule is the main bioactive product of the renin–angiotensin system, its inhibition is a key strategy for hypertension therapy. The aim of this study was to conduct an in silico evaluation of a series of new phthalamides as ACE inhibitors, examine the acute toxicity (in mice) of three of these molecules, and test the hypertensive effect of the most promising compound in a spontaneous hypertensive rat (SHR) model. The new phthalamide derivatives were synthesized with a fast, cheap, high-yield green (solventless) procedure. Three molecules (DD-01, DD-13, and DD-14S) from the current series of phthalamides were selected as the most promising ACE inhibitors based on in silico analysis of their physicochemical properties, Gibbs free energy and ADME profile. After synthesis, these three molecules showed low toxicity (LD50 > 1600 mg/kg) in the acute toxicity test (Lorke’s method). Finally, DD-01 significantly decreased systolic, diastolic, and mean arterial pressure in the SHR model, being ∼7-fold more potent than captopril (the reference drug). Three novel phthalamide derivatives were synthesized in good yields with a fast and efficient green procedure. They all displayed low toxicity. The one tested in the SHR model proved to be efficient for reducing blood pressure.


Hypertension Spontaneously hypertensive rats Green chemistry ADME profile Molecular docking 



EA-J is a postdoctoral fellow from CONACYT. This work was supported by PAPIIT IN223519 (to RV-M), PAPIIT IN226819 (to IAGO) DGAPA from the UNAM, by SIP (m1930 and 20194934) from the Instituto Politécnico Nacional, and by CONACYT-Mexico. We also thank MVZ L. Flores, MD. F. Barrón-Moreno, and Biol. TE Villamar-Duque from FES Iztacala, UNAM, for their aid in animal care and housing.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2327_MOESM1_ESM.docx (797 kb)
Supplementary Information.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Unidad de Investigación en Biomedicina, Carrera de Enfermería, Facultad de Estudios Superiores-IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantlaMexico
  2. 2.Laboratorio de Investigación en Bioquímica, Sección de Estudios de Posgrado e InvestigaciónEscuela Superior de Medicina del Instituto Politécnico NacionalMexico CityMexico
  3. 3.Departamento de Bioquímica, Facultad de MedicinaUniversidad Nacional Autónoma de México, Ciudad UniversitariaMexico CityMexico

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