Abstract
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.
Highlights
Phenylbutazone is a non-steroidal anti-inflammatory drug that has analgesic and antipyretic actions and can be used in some situations related do acute pain and muscular-skeletal disorders, such as in cases of ankylosing spondylitis and rheumatoid arthritis [1]
Our study shows that this toxicity is mainly related to their potential and Recently we have developed a theoretical prediction model of toxicity forionization pyrazolone drugs for nucleophilicity values, on electron transfer processis[8]
The Density Functional Theory (DFT) method was employed, using the B3LYP functional hybrid [58,59] and the 6-31+G(d,p) basis set to phenylbutazone derivatives (PD) which act as electron donating group
Summary
Phenylbutazone is a non-steroidal anti-inflammatory drug that has analgesic and antipyretic actions and can be used in some situations related do acute pain and muscular-skeletal disorders, such as in cases of ankylosing spondylitis and rheumatoid arthritis [1]. Group of pyrazolones, derived from enolic acid associated hydrogen α, α-dicabonylic. It was synthesized which in 1946are and introduced into clinical practicetoinits1949. Attributed severe restrictions on the use of phenylbutazone in humans, because of the recognition that It wasinduced synthesized in dyscrasias, 1946 and introduced into clinical practice in 1949. Agranulocytosis in 1980 were such a drug blood which includes aplastic anemia, leukopenia, attributed severe restrictions on the use of phenylbutazone in humans, because of the recognition and thrombocytopenia in some cases leading to death [3]
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