38229-00-4

Upstream product

• 1914-20-1 N-methoxyphthalimide 
• 64-04-0 phenethylamine 
• 85-44-9 phthalic anhydride 

Relevant academic research and scientific papers

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

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.]

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

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.

Nucleophilic reactions of N-hydroxy-,methoxy-,2,3-epoxypropoxy-phthalimides

Reaction of N-hydroxyphthalimide (4) with equivalent amounts of aliphatic and aromatic primary amines gives the N-substituted phthalimides (7), while with excess of these amines if gives the diamides (8) of phthalic acid.The reaction of 4 with t-butyl amine gives only the butyl monoamide (9a) of phthaloylhydroxamic acid.N-Methoxyphthalimide (5) reacts in the same manner.Compound 4 does not condense with epichlorohydrin, but condense with epibromohydrin to give N-(2,3-epoxypropoxy)phthalimide (6) which on reaction with equivalent amounts of aliphatic primary amines gives the N-substituted phthalimides (7) and with excess of the amines it gives the diamides (8) of phthalic acid.The reaction of 6 with aromatic primary amines gives only the N-arylphthalimides.Secondary amines do not react with 6.