A novel one pot Mannich synthesis of methylpiperidin phenols, methylphenylmorfolin phenols and methyltiophenylmorpholin phenols solvent-free and using infrared light irradiation

Velázquez, Alejandra; Torres, Luis A.; Díaz, Gaspar; Ramírez, Aldo Bazán; Hernández, Roberto Ramírez; H.Santillán,; Martínez, Luisa; Martı́nez, Ignacio; Díaz-Barriga, Sandra; Abrego, Víctor H.; M.A.Balboa,; Camacho, Brígida; López‐Castañares, R.; A.Dueñas-González,; Cabrera, G.; Ángeles, Enrique

doi:10.3998/ark.5550190.0007.218

Cited by 15 publications

(8 citation statements)

References 18 publications

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“…ACE inhibition has been proven to be effective in myocardial infarction, reducing complications, improving symptoms and attenuating the progression of cardiac insufficiency [8,10,11]. Additionally, ACE inhibitors attenuate not only the production of Ang II at a systemic and tissue level, but they also allow the accumulation of bradykinin because they inhibit its degradation [20,21,22,23].…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that TBTIF has a high affinity for ACE [10,33]. Furthermore, it is suggested that the increase in Ang(1-12) during this phase of infarction is to promote the production of components that counteract the damage caused to the heart, so that the production of Ang(1-7) and, as Ferrario et al [30] suggest, Ang(1-12) could be used as a quick-release substrate for the immediate production of the RAS components instead of being produced from angiotensinogen [8]. Burrell et al [34] showed that myocardial infarction generates an upregulation of mRNA of ACE and ACE2, as did we.…”

Section: Discussionmentioning

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].…”

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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…Considering Stout's work, our group purposed to change the pyrrolidine ring and used the morpholine and thiomorpholine systems instead. In 2007 we synthetized and characterized a group of compounds derived from phenol, named LQM300 [32]. These new compounds were tested in rat model [33], from which the compounds ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the inhibition of angiotensin-converting enzyme by new thiomorpholine compounds using capillary zone electrophoresis

Vázquez-Valadez

Cedillo

Carreño³

et al. 2019

J. Mex. Chem. Soc.

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Abstract. The inhibition capacity of the angiotensin converting enzyme (ACE) was determined by 5 different methylthiomorpholine compounds: (4-tert-butyl-2-(thiomorpholin-4-ylmethyl)phenol (LQM318), 4-tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol (LQM319), 3,5-bis(thiomorpholin-4-ylmethyl) pyrogallol (LQM322), 4-methoxy-2-thiomorpholin-4-ylmethyl-1-phenol (LQM328) and 3,6-bis(thiomorpholin-4-ylmethyl)benzene-1,2-diol (LQM329), using Captopril as a reference. This last drug is used as an antihypertensive agent and known for its biological effect over ACE. The study was done using the capillary electrophoresis technique, with an in-line reaction using hippuryl-histidyl-leucine (HHL) as substrate to produce hippuric acid (HA). HA was detected at 254 nm, which is the detection wavelength to get the quantification of this compound. That was performed under the experimental conditions reported for such interaction. From this, the electrophoretic mobility of hippuric acid was computed in order to deduce the effective migration time and the recovered quantity, to prove and quantify the in-line activity of the enzyme. Resumen. La capacidad de inhibición de la enzima convertidora de angiotensina (ACE) se determinó mediante 5 compuestos diferentes derivados de la metiltiomorfolina: (4-terc-butil-2- (tiomorfolin-4-ilmetil) fenol (LQM318), 4-tert-butil-2,6-bis ( tiomorfolin-4-ilmetil) fenol (LQM319), 3,5-bis (tiomorfolin-4-ilmetil) pirogalol (LQM322), 4-metoxi-2-tiomorfolin-4-ilmetil-1-fenol (LQM328), 3,6 -bis (tiomorfolin-4-ilmetil) benceno-1,2-diol (LQM329) usando como referencia al Captopril. Este fármaco es utilizado como agente antihipertensivo y conocido por su efecto biológico sobre la ACE. El estudio se realizó utilizando la técnica de electroforesis capilar, con una reacción en línea utilizando hippuril-histidil-leucina (HHL) como sustrato para producir ácido hipúrico (HA). El HA se detectó a 254 nm, que es la longitud de onda de detección para obtener la cuantificación de este compuesto. Eso se realizó bajo las condiciones experimentales reportadas para tal interacción. A partir de esto, se calculó la movilidad electroforética del ácido hipúrico para deducir el tiempo efectivo de migración y la cantidad recuperada, esto para probar y cuantificar la actividad en línea de la enzima.

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“…The bis(alkylaminomethyl) hydroquinones 6a-6c were prepared by Mannich reactions, i.e., the reaction of 1,4-hydroquinone with paraformaldehyde and the corresponding secondary amine. 47,48 We have determined the structures of 4b, 4c, and 4d ( Fig. 1) and 5a and 5b (Fig.…”

Section: Synthesis and Characterization Of Hydroquinonesmentioning

confidence: 99%

Unconventional redox properties of hydroquinones with intramolecular OH−N hydrogen bonds

et al. 2014

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The redox (chemical and electrochemical) properties of several hydroquinones are reported in which the OH protons are engaged in intramolecular hydrogen bonds to a nitrogen-based acceptor (pyridine or amine). The 1,4-hydroquinones generally undergo reversible oxidation to quinones in which both OH protons have transferred to the pendant bases; the oxidation processes are generally chemically and electrochemically reversible, in stark contrast with normal hydroquinones, which are oxidized irreversibly (via proton loss) to quinones. The oxidation processes, believed to occur in concerted proton/electron transfer steps, are at much lower potentials for the hydrogen-bonded derivatives relative to unsubstituted derivatives. In contrast, isomeric 1,3-hydroquinones (resorcinols) are oxidized irreversibly at relatively high potentials. The stability of some of the 1,4-hydroquinone oxidized species permits their isolation and characterization both spectroscopically and structurally. Somewhat surprisingly, in the oxidized species in which the proton is now located on the nitrogen base, the characterization data indicate that there is no NH−O hydrogen bond. Relationships between the particulars of the redox properties of the hydroquinones (potentials, reversibility/stability) and molecular structure are discussed.Résumé : Les propriétés redox (chimiques et électrochimiques) de plusieurs hydroquinones sont décrites, dans lesquelles les protons OH participent à des liaisons hydrogènes intramoléculaires avec un accepteur à base d'azote (pyridine ou amine). Les 1,4-hydroquinones subissent en général une oxydation réversible qui produit des quinones dans lesquelles les deux protons OH ont été transférés aux bases correspondantes. Les processus d'oxydation sont généralement chimiquement et électrochimique-ment réversibles, à l'opposé des hydroquinones normales qui sont oxydées de manière irréversible (par perte de proton) sous la forme de quinones. Les processus d'oxydation, dont on pense qu'ils se produisent selon des étapes de transfert concerté de proton/électron, présentent des potentiels beaucoup plus bas dans le cas des dérivés comportant des liaisons hydrogènes que dans celui des dérivés non substitués. En revanche, les 1,3-hydroquinones isomériques (résorcinols) sont oxydées de manière irréversible à des potentiels relativement élevés. La stabilité de quelques-unes des 1,4-hydroquinones oxydées permet de les isoler et de les caractériser structurellement et par spectroscopie. De façon quelque peu surprenante, les données de caractérisation indiquent que les espèces oxydées, dans lesquelles le proton est désormais situé sur la base azotée, ne possèdent pas de liaisons hydrogènes NH−O. Les liens entre les propriétés redox détaillées des hydroquinones (potentiels, réversibilité/stabilité) et la structure moléculaire sont analysés. [Traduit par la Rédaction]

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A novel one pot Mannich synthesis of methylpiperidin phenols, methylphenylmorfolin phenols and methyltiophenylmorpholin phenols solvent-free and using infrared light irradiation

Cited by 15 publications

References 18 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

Evaluation of the inhibition of angiotensin-converting enzyme by new thiomorpholine compounds using capillary zone electrophoresis

Unconventional redox properties of hydroquinones with intramolecular OH−N hydrogen bonds

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