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.Key words: acetaminophen, analgesic effect, ligand-based drug design, molecular modeling, opioid derivatives Received 14 December 2011, revised 14 February 2012 and accepted for publication 25 February 2012 Acetaminophen (ACP) or paracetamol is a widely used over-thecounter analgesic and antipyretic drug, and it appears to be safe when administered according to the therapeutic dosage. However, when an overdose is taken, it produces hepatic and ⁄ or renal injury in humans and in experimental animals (1,2). The pharmacological effects are generally considered to be based on the inhibition of prostaglandin synthesis (3-5). The cyclooxygenase (COX)-inhibiting activity was suggested to be related to its capacity to quench the tyrosyl radical present in prostaglandin endoperoxide synthase (PGES) (6), as shown in Figure 1.This drug is metabolized primarily by glucuronidation and sulfation. Nevertheless, a small amount is probably metabolized via a third metabolic pathway, through an oxidation by the microsomal cytochrome P450-containing mixed-function oxidase system to form Nacetyl-p-benzoquinone-imine (NAPQI). 1,4-Michael adduct of NAPQIglutathione and the corresponding cysteine conjugate and mercapturic acid breakdown products were found in human urine after the ingestion of ACP. However, hepatotoxic activity appears to be limited to compounds that are capable of forming quinoid structures, which are susceptible to both irreversible and reversible attack by soluble and non-soluble thiols (7-9).Many reports describe investigations that aim at performing structural modifications of the ACP scaffold to improve its analgesic and safety properties. Besides efforts to modulate its toxicity or to understand the toxic mechanism, important progress has been made as well by modifying the substituents to generate homologous and congeners obtained by alkylations, halogenations, and addition ...

Regioisomerism and 5-substitution as promising approaches for molecular design of safer acetaminophen derivatives

“…In the same way, EWGs (-F, -Cl, and -NO 2 ) increased BDE NH values for 91.52 (7), 91.69 (8), and 92.81 kcal/mol (9). These results show that all regioisomers would be less toxic than acetaminophen [21].…”

Synthesis and Characterization of New Functionalized 1,2,3-Triazole-Based Acetaminophen Derivatives via Click Chemistry from Expired Commercial Acetaminophen Tablets

“…As a consequence, research on new APAP derivatives is an active area of drug development [15][16][17][18][19][20][21][22][23][24][25][26]. According to current reports, a structural modification of the N-acetylp-aminophenol skeleton can improve, reduce, or even change the enzymatic activities of a drug and, thus, the pharmacological properties including cytotoxicity.…”