Synthesis and antihypertensive effects of new methylthiomorpholinphenol derivatives

Velázquez, Alejandra; Martínez, Luisa; Abrego, Víctor H.; Balboa, Marı́a A.; Torres, Luis A.; Camacho, Brígida; Díaz-Barriga, Sandra; Romero, A.; López‐Castañares, R.; Ángeles, Enrique

doi:10.1016/j.ejmech.2007.04.003

Cited by 27 publications

(20 citation statements)

References 17 publications

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“…A second dose of the agents was given 24 h after coronary artery ligation in conscious rats. The doses of these drugs were chosen on the basis of previous studies that showed a reduction of systolic pressure, diastolic pressure and heart rate in rats that were anesthetized and cannulated with a catheter (PE50) connected to a pressure transducer that fed into a Digi-Med blood pressure analyzer [9]. …”

Section: Methodsmentioning

confidence: 99%

“…Compounds with possible activity as ACE inhibitors have been derived from febrifugine, a quinazolinone alkaloid first isolated from the Chinese herb Dichroa febrifuga [8,9]. 4-Tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol (TBTIF) is a new compound that in preclinical studies showed antihypertensive effects comparable to captopril [9,10]. Since the mechanism for the actions of TBTIF has not been determined, we undertook to investigate its effects on components of the circulating RAS and bradykinin following occlusion of a coronary artery.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Effects of a Novel Angiotensin-Converting Enzyme Inhibitor versus Captopril on Plasma Angiotensins after Myocardial Infarction

Flores-Monroy

Ferrario²,

Valencia-Hernández³

et al. 2014

Pharmacology

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The compound 4-tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol (TBTIF) has molecular characteristics similar to angiotensin-converting enzyme (ACE) inhibitors of the sulfhydryl subclass. To assess its value as a new therapeutic agent, we performed a comparative analysis of the effect of TBTIF versus captopril on the circulating levels of angiotensin (Ang) peptides and bradykinin as well as ACE and ACE2 expression after myocardial infarction. Male Wistar rats were divided into four groups: (1) sham-operated rats; (2) rats subjected to 48 h of coronary artery ligation; (3) rats administered captopril (1 mg/kg, i.m.), and (4) a similar group of rats given TBTIF (1 mg/kg, i.m.). Both drugs were administered 30 min before coronary artery ligation and again 24 h later. Acute myocardial infarction lowered both systolic and left ventricular systolic blood pressures compared to the sham group and increased plasma levels of Ang I, Ang II, Ang(1-7) and Ang(1-12). Administration of either captopril or TBTIF reversed the increases in plasma angiotensins. Interestingly, the levels of plasma Ang(1-7) achieved by administration of TBTIF reached values higher than those recorded with captopril. Both agents reversed the decreases in plasma concentrations of bradykinin; in addition, TBTIF upregulated ACE expression, while both agents suppressed the ACE2 upregulation induced by myocardial infarction. These results demonstrate a beneficial effect of the novel compound TBTIF in suppressing the acute surge in the circulating renin-angiotensin system activity induced by myocardial infarction. The greater effects of this compound in augmenting plasma Ang(1-7) concentrations may be highly significant as drugs which augment the concentration of this heptapeptide will exert cardioprotective actions in part by suppressing the hypertrophic and profibrotic actions of Ang II.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative Effects of a Novel Angiotensin-Converting Enzyme Inhibitor versus Captopril on Plasma Angiotensins after Myocardial Infarction

Flores-Monroy

Ferrario²,

Valencia-Hernández³

et al. 2014

Pharmacology

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“…On the other hand, evidence suggests that morpholine compounds have an antiproliferative effect [18][19][20][21]. LQM319 is a thiomorpholine compound that, as we showed in a previous report, has antihypertensive activity, similar to captopril [1]. Recent studies suggest that it also has an antiproliferative effect.…”

Section: Introductionmentioning

confidence: 97%

Molecular Docking of 4-Tert-buthyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol (LQM319) on Fas Receptor (CD95)

Zuñiga¹,

Vázquez²,

Velázquez³

et al. 2013

JCT

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The balance between cell proliferation and cell growth characterizes tissue homeostasis on one side and cell death on the other side. Fas receptor-mediated apoptosis is a control mechanism for tissue homeostasis, and avoiding this death pathway predisposes to many human diseases, including cancer. Current therapies for this disease are invasive and do not have the desired effect in the control of the disease. In this context, the search for new drugs that contribute to a better treatment is gaining more relevance. 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol (LQM319) [1,2] is a drug currently in preclinical stage, and we have shown that it has a hypertensive effect, similar to captopril, in a hypertensive rat model. Different studies have shown that some chemicals that are used as antihypertensive agents have an antineoplastic effect against certain types of cancer, as is the case of hydralazine [3], and captopril [4], among others [5]. On the other hand, it has been reported that morpholine derivatives may activate Fas (CD95)-mediated apoptosis. The aim of the present study was to show the interaction between CD95 (receptor) and thiomorpholine derivatives (ligand) using molecular modeling and docking studies, and to elucidate the possible action mechanism of 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol.

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“…5,6 The structure was characterized by infrared, 1 H-nuclear magnetic resonance and 13 C-nuclear magnetic resonance spectroscopy studies. 7 One of these agents is 4-tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol (TBTIF), and it was obtained by changing the pyrrolidine rings to methylthiomorpholin rings and by taking the phenol and methylpyrrolidine rings as a structural requirement to show cardiovascular effects. [7][8][9][10] However, there is little evidence about its pharmacological properties.…”

Section: Introductionmentioning

confidence: 99%

Antihypertensive Properties of a Novel Morphologic Derivative (4-tert-buthyl-2,6-bis(thiomorpholine-4-ilmethyl)phenol)

Martínez-Aguilar

Lezama-Martínez

Orozco-Cortés

et al. 2016

Journal of Cardiovascular Pharmacology

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We evaluated the antihypertensive properties of 4-tert-buthyl-2,6-bis(thiomorpholine-4-ilmethyl)phenol (TBTIF). Spontaneously hypertensive rats were treated with TBTIF or captopril (both at 1 mg·kg⁻¹·d⁻¹ intramuscularly for 4 days), and their blood pressure (BP) was assessed. In some experiments, concentration response curves to angiotensin I or angiotensin II were generated in rat aortic rings and in the absence or presence of Ang-(1-7), N(G)-monomethyl L-arginine, or both; additionally, the angiotensin-converting enzyme (ACE) and ACE2 mRNA levels were quantified in the aortic rings using reverse transcription-polymerase chain reaction. TBTIF diminished BP and reduced angiotensin I- or angiotensin II-induced vasoconstriction. The presence of Ang-(1-7) induced a greater reduction in vasoconstriction, and this effect was reversed by L-N(G)-monomethyl arginine. Moreover, TBTIF decreased the mRNA of ACE and increased the mRNA of ACE2. In conclusion, TBTIF diminished rat BP through nitric oxide-dependent and nitric oxide-independent mechanisms. In contrast to captopril, TBTIF exhibits better antihypertensive properties through mechanisms that involve ACE2.

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Synthesis and antihypertensive effects of new methylthiomorpholinphenol derivatives

Cited by 27 publications

References 17 publications

Comparative Effects of a Novel Angiotensin-Converting Enzyme Inhibitor versus Captopril on Plasma Angiotensins after Myocardial Infarction

Comparative Effects of a Novel Angiotensin-Converting Enzyme Inhibitor versus Captopril on Plasma Angiotensins after Myocardial Infarction

Molecular Docking of 4-Tert-buthyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol (LQM319) on Fas Receptor (CD95)

Antihypertensive Properties of a Novel Morphologic Derivative (4-tert-buthyl-2,6-bis(thiomorpholine-4-ilmethyl)phenol)

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