Desenho racional e síntese de análogos do fármaco propafenona

Abstract

Propafenone is an antiarrhythmic drug used in the treatment of supraventricular and ventricular arrhythmias. It acts primarily as a sodium channel blocker and, to a lesser extent, as a β-AR antagonist. One issue with sodium channel-targeting antiarrhythmic drugs currently in clinical use is the adverse effects related to cardiac and extracardiac toxicity. Therefore, the development of low-toxicity antiarrhythmic drugs is necessary. One of the main strategies to reduce the toxicity of a given drug is the synthesis of analogs. In this context, the present study proposed the design and synthesis of propafenone analogs. The design of the analogs was guided by SAR analysis and in silico approaches, including the prediction of ADMET properties using the ADMETlab server and molecular docking simulations with the AutoDock Vina program, having as targets the proteins sodium channel Nav1.5, β1-AR, and β2-AR. From SAR analysis, four propafenone analogs were proposed, containing an amino group at position 5 of ring A and saturated nitrogen heterocycles replacing the propylamino group. Pharmacokinetic and toxicological predictions indicated that the analogs have good oral bioavailability and low hepatotoxicity. Molecular docking simulations indicated that analogs rac-6c and rac-6d interact strongly with the targets sodium channel Nav1.5, and β1-AR, with analog rac-6d also interacting strongly with the β2-AR target. Based on these findings, analog rac-6c was selected for synthesis. The commercial substrate 1-(2-hydroxyphenyl)-3-phenylpropan-1-one was initially nitrated at position 5 of ring A. Then, the phenolic group was alkylated with epichlorohydrin, and the epoxide ring was opened in the presence of HCl. Subsequently, the nitro group was selectively reduced using Fe0 nanoparticles. Finally, the key intermediate was aminated with piperidine, yielding the analog rac-6c with an overall yield of 48%.