Docking Studies of Methylthiomorpholin Phenols (LQM300 Series) with Angiotensin-Converting Enzyme (ACE)

Vázquez-Valadez, V.H.; Abrego, Víctor H.; Martínez, Pablo A; Torres, Gustavo; Zuñiga, Oscar; Escutia, Daniel; Vilchis, Rebeca; Velázquez, Alejandra; Martínez, Luisa; Ruiz, M. C. M.; Camacho, Brígida; López‐Castañares, R.; Ángeles, Enrique

doi:10.2174/1874104501307010030

Cited by 6 publications

(6 citation statements)

References 10 publications

(10 reference statements)

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“…Such an increase may be due to the resulting accumulation of Ang I and due to the inhibition of Ang-(1-7) metabolism. 31,33,34 Owing to the fact that TBTIF has ACE affinity, 10 and produced similar effects to that obtained with captopril, our results suggest that this compound is an ACE inhibitor. This research shows that the treatment of SHR rats with TBTIF or captopril induced an antihypertensive effect (Table 1).…”

Section: Discussionsupporting

confidence: 76%

“…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. In this sense, docking studies showed that the compound, compared with captopril, has higher affinity for angiotensinconverting enzyme (ACE).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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Section: Discussionsupporting

confidence: 76%

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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“…It is evident that is necessary to search for an accurate inhibitor due to the clinical relevance of the ACE activity. Different techniques have been applied, to reach that objective, such as spectrophotometry [6,7], fluorometry [8] or radioisotopic [9,10] methods, besides some theoretical studies have been carried out to predict the possible interaction of new compounds and compare them with the ones already available in the market [11]. The methods of separation and quantification through HPLC started to be developed because of the complicated separation of hippuric acid through the extraction with dissolvent; added to this the separation could not be performed completely [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…2), were the best candidates from a series of 25 tested molecules. The computational studies previously described [11] indicated a similarity of its biological activity with Captopril and its inhibition is known to act at the level of the ACE, this group of compounds were protected through a patent [33].…”

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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“…Vázquez-Valadez et al [16] reported that main target in the treatment of hypertension is the ACE. This enzyme is responsible for producing angiotensin II, a potent vasoconstrictor.…”

Section: Resultsmentioning

confidence: 99%

Virtual Screening of Heterocyclic Compounds Against Angiotensin-Converting Enzyme for Potential Antihypertensive Inhibitors

A²,

Shanmugam³

2019

Asian J Pharm Clin Res

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Objective: The objective of this study was to investigate the antihypertensive activity of heterocyclic compounds against angiotensin-converting enzyme (ACE) through molecular docking studies. Methods: The X-ray crystal three-dimensional (3D) structure of human ACE complexed with lisinopril (PDB ID: 1O86) was retrieved from protein databank. The two-dimensional structures of 10 selected heterocyclic compounds were drawn in ACD-Chemsketch and converted into 3D structures. The 3D structures of compounds were virtually screened in the binding pockets of ACE using FlexX docking program. Further, the chemical entities revealing the molecular electronic structures of the best docked compound (Compound-4) were explored through density functional theory studies. Results: The Compound-4 showed the highest docking score of −26.6290 kJ/mol with ACE. The Hbond and non-bonded interactions are favored by phenylalanine, leucine, and arginine. The energy gap of 1.60 eV between highest occupied molecular orbital and lowest unoccupied molecular orbitals explained the presence of strong electron-acceptor group. Furthermore, the molecular electrostatic potential studies clearly envisaged the requirement of electropositive and electronegative groups are crucial for the ACE inhibitor activities. Conclusion: The identification of good ACE inhibitors requires the understanding of the current ACE inhibitors. Thus, the docking interactions of Compound-4 and its molecular electronic structure significantly imply its potential as antihypertensive agent. However, further clinical studies are required to ascertain its potential toxic effects.

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Docking Studies of Methylthiomorpholin Phenols (LQM300 Series) with Angiotensin-Converting Enzyme (ACE)

Cited by 6 publications

References 10 publications

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

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

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

Virtual Screening of Heterocyclic Compounds Against Angiotensin-Converting Enzyme for Potential Antihypertensive Inhibitors

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