Síntese e avaliação farmacológica de novos derivados benzofenônicos como candidatos a fármacos anti-inflamatórios

Abstract

Inflammation is a reaction of the body to infection or tissue damage, in which cells are triggered and act in the direction of inactivate or destroy invading microorganisms, and initiate the tissue repair process. Several diseases have been associated with inflammation, which arouses great interest in the search for anti-inflammatory drugs. Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID), has the benzophenonic nucleus in its structure and has its action in inhibiting the synthesis of prostaglandins, being known for its dual action on cyclooxygenase isoforms, COX -1 and COX-2. The withdrawal from the market of antiinflammatory drugs that had severe side effects made evident the need for the search for new substances that have a reduced number of side effects. In view of the good results obtained from previous studies with natural and synthetic benzophenones in the anti-inflammatory evaluation added to the ketoprofen structure, the synthesis of new benzophenones was planned. In this work the synthesis and characterization of 43 derivatives are described, of which 19 are unpublished. Benzophenones 1g-1i were obtained by Friedel-Crafts acylation reaction, and benzophenone 1j obtained by oxidation. The derivatives 2a-j, 4a-f and 5a-f were obtained under similar conditions by the reaction of benzophenones with thiosemicarbazide, semicarbazide hydrochloride and aminoguanidine bicarbonate, respectively. In addition, the synthesis of thiazole heterocyclic derivatives (3a-j) is also described by intramolecular cyclization reaction. Derivative 6 was obtained by radical substitution reaction with 4- methylbenzophenone and N-bromosuccinimide and was used as substrate to obtain the imidazole derivatives 7 and azide 8. The reaction of the derivative 8 with 4 different alkynes under suitable conditions allowed 4 new benzophenone triazole derivatives, obtained by "click" cycloaddition reactions. All the derivatives were submitted to the evaluation of the anti-inflammatory activity by the mouse ear edema test induced by chrotonic oil and the evaluation of neutrophil recruitment. Thiazol derivatives have a potent effect in terms of reduction of ear edema. In addition, derivatives 2e, 3a and 3c inhibit concomitantly ear edema and neutrophil recruitment. Thus, these dual anti-inflammatory properties have shown a mechanism of action that differs from the usual anti-inflammatory agents. Substances with this mechanism of action may be more effective and have fewer side effects than commercial anti-inflammatory drugs.