CHEMICAL ADVANCES ON DESIGN AND DEVELOPMENT OF PARACETAMOL DERIVATIVES. Acetaminophen or paracetamol is a widely used analgesic and antipyretic drug and appears to be safe if used at normal therapeutic doses, but in large doses produce liver and / or kidney damage in humans and experimental animals. Prostaglandin endoperoxide synthase (PGES) and cytochrome P-450 are the key enzymes in humans as they are responsible for the analgesic and toxicity effects of paracetamol, respectively. At present, the development of new derivatives still has few impacts on clinical applications of safe compounds. Thus, in this work are discussed, a series of approaches on the design and development of acetaminophen derivatives. Some efforts were realized in our own research group.

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The molecular mechanism of cytoprotective effect on human erythrocytes of aminophenol and salicylates associated derivatives was related to their antioxidant capacity. The oxidative hemolysis induced by water-soluble free-radical initiator 2,2’-azobis-(2-amidine-propane)-dihydrochloride (AAPH) was inhibited by drug candidates named benzaminophen (BZL), salicytamide or 5-acetamide-salicylic acid (ASL), and salibenzamide or 5-benzamide-salicylic acid (BSL) when compared to their parents salicylic acid (SAC) and acetaminophen (ACP). Trolox (TLX) was the most powerful compound and used as positive control. BZL showed a potent effect followed by ACP > BSL > ASL. SAC did not show protective effect in any evaluated concentrations. These results are in accordance with the molecular mechanism by using theoretical calculation of single electron transfers (SET), hydrogen atom transfers (HAT), and sequential proton loss electron transfer (SPLET) by means of DFT/B3LYP/6-31++G(d,p) level of theory. [1,5] Hydrogen shift between carboxyl and phenol moieties and electronic properties related to pKa and other physicalchemical properties can be involved. The molecular association approach provides protective compounds more effective than SAC.

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