A Combined Study Using Ligand-Based Design, Synthesis, and Pharmacological Evaluation of Analogues of the Acetaminophen Ortho-Regioisomer with Potent Analgesic Activity

• Published in: Chemical biology & drug design 2012-07, Vol.80 (1), p.99-105
• Main Authors: Queiroz, Luana M. D., Rocha, Josmar R., Leitão, Andrei, Montanari, Carlos A., da Silva, Albérico B. F., Sousa, Pergentino J. C., Borges, Rosivaldo S.
• Format: Article
• Language: English
• Subjects: acetaminophen; Acetaminophen - analogs & derivatives; Acetaminophen - chemical synthesis; Acetaminophen - pharmacology; analgesic effect; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Constriction; Drug Design; ligand-based drug design; Ligands; Male; Mice; Models, Molecular; molecular modeling; Nociception - drug effects; opioid derivatives; Stereoisomerism
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2012.01372.x

A ligand‐based drug design study was performed to acetaminophen regioisomers as analgesic candidates employing quantum chemical calculations at the DFT/B3LYP level of theory and the 6‐31G* basis set. To do so, many molecular descriptors were used such as highest occupied molecular orbital, ionization potential, H–O bond dissociation energies, and spin densities, which might be related to quench reactivity of the tyrosyl radical to give N‐acetyl‐p‐benzosemiquinone‐imine through an initial electron withdrawing or hydrogen atom ion. Based on this in silico work, the most promising molecule, orthobenzamol, was synthesized and tested. The results expected from the theoretical prediction were confirmed in vivo using mouse models of nociception such as writhing, paw licking, and hot plate tests. All biological results suggested an antinociceptive activity mediated by opioid receptors. Furthermore, at 90 and 120 min, this new compound had an effect that was comparable to morphine, the standard drug for this test. Finally, the pharmacophore model is discussed according to the electronic properties derived from quantum chemistry calculations. The first drug design of analgesic candidates using DFT methods. The interaction between candidates and prostaglandin endoperoxide synthase were measured by OH bond dissociation energies. Theoretical prediction is confirmed by biological evaluation. Ortho regioisomer, named orthobenzamol (OBZ), has better analgesic activity compared with acetaminophen and can be related with opioid effect of morphine.