A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13–15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13–15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.

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.

Acetaminophen is a widely used over-the-counter analgesic and antipyretic drug, but in large doses can produce hepatic and/or renal injury. Based on its human toxicity by N-acetyl-p- benzoquinone imine formation as reactive toxic intermediate, an acetaminophen regioisomer substituted on 5-position, named chloraminophen, was proposed. The electron and hydrogen transfers were related to the ionization potential and bond dissociation energies on phenol and acetamide moieties. These calculations were performed by using quantum chemical calculations at the density functional theory (DFT/B3LYP) with the 6-311 + + G(d,p) basis set. For acute toxicity study was performed using a single dose test of 300 or 2000 mg/kg. No differences were found in the biochemical parameters except for aspartate aminotransferase levels, probably due to corn oil used as dilution solvent. The second energy of hydrogen abstraction may have great impact on amino-phenols toxicity. The regioisomerism can be a useful strategy in drug design for safer acetaminophen derivatives.