Original article Synthesis and pharmacological evaluation of N-phenyl-acetamide sulfonamides designed as novel non-hepatotoxic analgesic candidates Maria Letı ´cia de Castro Barbosa a, b , Gabriela Muniz de Albuquerque Melo c , Yolanda Karla Cupertino da Silva c , Raquel de Oliveira Lopes a, b , Everton Teno ´ rio de Souza c , Aline Cavalcanti de Queiroz c , Salete Smaniotto d , Magna Suzana Alexandre-Moreira c, * , Eliezer J. Barreiro a, b , Lı ´dia Moreira Lima a, b, ** a LASSBio 1 – Laborato ´rio de Avaliaça ˜o e Sı ´ntese de Substa ˆncias Bioativas, Faculdade de Farma ´cia, Universidade Federal do Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil b Po ´s-graduaça ˜o em Quı ´mica, Instituto de Quı ´mica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil c LaFI – Laborato ´rio de Farmacologia e Imunidade, Instituto de Cieˆncias Biolo ´gicas e da Sau ´de, Universidade Federal de Alagoas, Maceio ´, AL, Brazil d Laborato ´rio de Imunohistologia – Setor de Histologia, Instituto de Cieˆncias Biolo ´gicas e da Sau ´de, Universidade Federal de Alagoas, Maceio ´, AL, Brazil article info Article history: Received 2 December 2008 Received in revised form 23 February 2009 Accepted 25 February 2009 Available online 4 March 2009 Keywords: Analgesic LASSBio-1300 N-Phenyl-acetamide sulfonamides Paracetamol Hepatotoxicity abstract In this paper we report the design, synthesis and pharmacological evaluation of a series of N-phenyl- acetamide sulfonamide derivatives (5a–g), planned by structural modification on the prototype paracetamol (1). In this series (5a–g), compound LASSBio-1300 (5e; ID 50 ¼ 5.81 mmol/kg) stands out as a new non-hepatotoxic analgesic drug candidate. The increase of area, volume and eletrostatic potential of paracetamol’s analogues seems to be beneficial to the analgesic activity. Unlike paracetamol (1) and the other analogues (5a, 5d–g), compounds 5b and 5c presented an important anti-hypernociceptive activity associated to inflammatory pain. Ó 2009 Elsevier Masson SAS. All rights reserved. 1. Introduction Paracetamol (acetaminophen, 4-hydroxyacetanilide, 1) was synthesized in 1878 and the first clinical use was reported in 1893, but only after it was identified as the active metabolite of phen- acetin (2) and acetanilide (3) that it was marketed as a drug [1]. Introduced worldwide in the 1950s as an antipyretic and analgesic drug, paracetamol (1) is still one of the most popular over-the-counter drugs, which is frequently used on a prescription basis for the relief of acute and chronic pain. Within the thera- peutic range, it is, usually, well tolerated, with few side effects. However, when taken in over dosage, paracetamol (1) may cause severe and sometimes fatal hepatic necrosis [2,3]. The mechanism of paracetamol’s hepatotoxicity is well known and is directly associated to its hepatic metabolism. It is primarily metabolized by the liver, being 90% eliminated as glucoronide and sulphate metabolites, 5% excreted unchanged and 5% oxidized, by cytochrome P4502E1 (CYP2E1), to N-acetyl-p-benzoquinone imine (NAPQI) (Scheme 1) [4]. Hepatotoxicity arises only through NAPQI (4), a highly reactive compound that normally conjugates with glutathione, being eliminated as an inactive metabolite. However, in conditions where the production of NAPQI exceeds that of glutathione, this reactive metabolite binds covalently to liver proteins and causes dose-related liver injury by centrilobular necrosis [5,6]. In a continuing effort to develop new analgesic drug candidates, we report in this paper the design, synthesis and pharmacological evaluation of N-phenyl-acetamide sulfonamide derivatives (5a–g), planned by structural modification on the prototype paracetamol (1). The design concept considered the need to carry out structural modifications in the toxicophoric unit of paracetamol (1), avoiding its biotransformation to the reactive metabolite NAPQI (4). The structural design of this new series was accomplished first by applying a non-classical bioisosterism [7], represented by the * Corresponding author. ** Corresponding author. Po ´ s-graduaça ˜o em Quı ´mica, Instituto de Quı ´mica, Uni- versidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Tel.: þ55 2125626503; fax: þ55 2125626644. E-mail addresses: msamoreira@yahoo.com (M.S. Alexandre-Moreira), lidia@ pharma.ufrj.br (L.M. Lima). 1 http://www.farmacia.ufrj.br/lassbio/. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2009.02.026 European Journal of Medicinal Chemistry 44 (2009) 3612–3620