Planejamento, Síntese e Caracterização de Novos Candidatos a Protótipos de Fármacos Análogos a Amilorida

Abstract

Cardiovascular diseases, such as ischemic heart disease and hypertension, are the main causes of death worldwide. In Brazil, approximately 400,000 people lost their lives due to cardiovascular diseases in 2022. The use of multi-target medications to control hypertension increases adherence to medication, contributing to the success of treatment. Therefore, efforts are being made to develop prototype medicines that act on different targets. In this sense, the LQFM 021 prototype demonstrated vasorelaxant, antihypertensive, analgesic and anti-inflammatory activity. On the other hand, the drug amiloride, used in antihypertensive therapy as a diuretic, also has cardioprotective activity. Therefore, the objective of this work was to synthesize and elucidate the chemical structure of 10 compounds indicated as candidate drug prototypes, with possible cardioprotective and antihypertensive activity. To this end, the molecular hybridization strategy was used between the compounds LQFM 021 and amiloride. Five compounds were synthesized in 5 steps, another five compounds were synthesized in 4 steps. The methods obtained global yields ranging between 9 and 30%. The compounds obtained were structurally characterized by NMR, infrared and x-ray diffraction techniques. The chemical shifts of 1H and 13C of the compounds obtained indicate the success of the reactions. Spectra in the IR region of the compounds reveal C=O stretching frequencies in the range of 1700-1640 cm-1, decreasing the presence of the amide functional group. Furthermore, X-ray diffraction studies confirmed the structure of the compounds LQFM 340 and LQFM 336, which crystallize in a monoclinic system as space group P21/c, with molecular formulas C11H13N5O2 and C11H12FN5O, respectively. The in-silico prediction of the physicochemical properties and toxicity of the compounds was obtained using the Molinspiration and Osiris software. The physicochemical parameters indicate that the compounds have good oral absorption and low toxicity. Further studies will evaluate the cardioprotective/antihypertensive activities of the compounds obtained in this work