title: A combined study using ligand-based design, synthesis, and pharmacological evaluation of analogues of the acetaminophen ortho-regioisomer with potent analgesic activity.
abstract: 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 abstraction. 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.
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Instituto de Ciências da Saúde, Universidade Federal do Pará, Augusto Correa, SN, 66075-110 Belém, PA, Brazil.
authors.forename: Luana M D
authors.initials: LM
authors.lastname: Queiroz
authors.forename: Josmar R
authors.initials: JR
authors.lastname: Rocha
authors.forename: Andrei
authors.initials: A
authors.lastname: Leitão
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Montanari
authors.forename: Albérico B F
authors.initials: AB
authors.lastname: da Silva
authors.forename: Pergentino J C
authors.initials: PJ
authors.lastname: Sousa
authors.forename: Rosivaldo S
authors.initials: RS
authors.lastname: Borges
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003250:Constriction; D015195:Drug Design; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D059225:Nociception / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D008024:Ligands; D000082:Acetaminophen