Modificação estrutural de fármacos: Síntese de derivados da Sulfanilamida e Tacrina contendo selênio

Abstract

In the present work, the structural modification of two important drugs is described: Tacrine and Sulfanilamide. In both cases, an organic portion of selenium is added to the structures to reduce their adverse effects. Through oxidative catalysis using a DMSO/I2 system, it was possible to perform the selenylation of anilines in short reaction times. First, the synthesis of 4-amino-3 (arylselanyl)benzenesulfonamides was carried out through the reaction between 4-aminobenzenesulfonamide and diorganyl dichalogenides using molecular iodine catalysis (10 mol%), DMSO as an oxidant agent (3 equiv.) for a period of six hours at 110°C. Under this condition, seventeen examples were obtained with yields ranging from 54% to 98%, containing electron-donating and withdrawing groups attached to the aromatic ring, besides bulky, sterically hindered and alkyl groups. The 4-amino-3-(phenylselanyl)benzenesulfonamide could be applied in the synthesis of more complex molecules, containing the 1,2,3-triazole unit in good yields (54% and 95%). Additionally, the compound synthesized using diphenyl diselenide as a precursor was evaluated against acute inflammatory pain, demonstrating promising antinociceptive property. This suggests that the compound may be an efficient and potent prototype for the treatment of acute pain conditions. FÓRMULA In the second work, initially the synthesis of 2-aminobenzonitriles containing an organic portion of selenium was carried out using the same method of the previous work, however, with a smaller amount of molecular iodine (5 mol%). In this case, sixteen compounds were obtained containing aryl, butyl and naphthyl substituents linked to the portion derived from diorganyl diselenide, in good yields (40 – 90%). Subsequently, these compounds were used as substrates in the reaction with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as Lewis acid, to carry out the synthesis of selenylated analogues of Tacrine, a drug used as a reversible inhibitor of acetylcholinesterase (AChE). The desired products were obtained in 20% to 87% yields. In addition, all synthesized products were analyzed by molecular docking for their bond affinity with the AChE enzyme. Some compounds studied showed higher score values than Tacrine, which indicates a high potential for AChE inhibition, making them relevant therapeutic targets. FÓRMULA