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A main target in the treatment of hypertension is the angiotensin-converting enzyme (ACE). This enzyme is responsible for producing angiotensin II, a potent vasoconstrictor. Therefore, one of the targets in the treatment of hypertension is to inhibit ACE activity. Hence, this study’s aim is to use computational studies to demonstrate that the proposed heterocyclic compounds have a molecular affinity for ACE and that, furthermore, these heterocyclic compounds are capable of inhibiting ACE activity, thus avoiding the production of the vasopressor Angiotensin II. All this using computer-aided drug design, and studying the systems, with the proposed compounds, through molecular recognition process and compared with the compounds already on the market for hypertension.

Ethyl-4-bromophenyl-carbamate (LQM 919) and Ethyl-4-chlorophenyl-carbamate (LQM 996) are compounds that inhibit egg-laying and hatching of tick larvae that are resistant to conventional ixodicides. The structure-activity relationship (SAR) to get the endpoint predictions of mutagenicity and carcinogenicity of the LQM 919 and LQM 996 was performed and the absence of mutagenicity was confirmed by Ames test. SAR analysis show no structural alerts indicating the ability of ethyl-carbamates to bind biomolecules or estrogen receptors. Endpoint of mutagenicity with and without metabolic activation showed that the ethyl-carbamates were negative (p <0.05) for mutagenicity induction in strains TA97, TA98, TA102, TA1535, TA1537 and TA1538 of Salmonella typhimurium. Pre-incubation with different ethyl-carbamate concentrations did not increase the number of spontaneously reverting colonies; moreover, the compounds did not induce a concentration-dependent increase in the number of reverting colonies in any of the strains used. This confirmed the absence of mutagenic activity in this test system. Exogenous metabolic activation did not modify these observations; suggesting that no metabolites with mutagenic activity were present. The endpoint of carcinogenicity in rats were negative for LQM 919 (p <0.05,) and LQM 996 (p <0.001). The results of the present study strongly suggest that ethyl-carbamates do not represent a risk for cancer in mammals.

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.