New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives Gildasio A. Silva, a,b,z Luciana M. M. Costa, a Fernanda C. F. Brito, a Ana L. P. Miranda, a Eliezer J. Barreiro a,b and Carlos A. M. Fraga a, * a Laboratorio de Avaliac ß~aoeSıntese de Subst^ancias Bioativas (LASSBio), Faculdade de Farmacia, Universidade Federal do Rio de Janeiro, PO Box 68023, 21944-971, Rio de Janeiro, RJ, Brazil b Nucleo de Pesquisas de Produtos Naturais (NPPN), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil Received 7 February 2004; revised 19 March 2004; accepted 7 April 2004 Abstract—In this work, we reported the synthesis and evaluation of the analgesic, antiinflammatory, and antiplatelet properties of new phenothiazine-attached acylhydrazone derivatives (6), designed exploring the molecular hybridization approach between antipsychotic chlorpromazine (4) and other heterocyclic derivatives (3) and (5) developed at LASSBio. Target compounds were synthesized in very good yields exploiting diphenylamine (7) as starting material, through regioselective functionalization of the C-1 position of 10H-phenothiazine ring. The evaluation of platelet antiaggregating profile lead us to identify a new potent prototype of antiplatelet derivative, that is (6a) (IC 50 ¼ 2.3 lM), which acts in arachidonic acid pathway probably by inhibition of platelet COX-1 enzyme. Additionally, the change of para-substituent group of acylhydrazone framework permitted us to identify hydrophilic carboxylate derivative (6g) and hydrophobic bromo derivative (6b) as two new leads of analgesics more active than dipyrone used as standard and with selective peripheral or central mechanism of action. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Hydrazone (B, Fig. 1) and acylhydrazone (C, Fig. 1) moieties are the most important pharmacoforic cores of several antiinflammatory, antinociceptive, and anti- platelet derivatives developed at LASSBio. 1 The bio- logical profile of compounds presenting this subunit are related to its relative acidity and its capacity to stabilize free radicals, mimicking bis-allyl fragment (A, Fig. 1) of certain unsaturated fatty acids, for example, arachidonic acid (1), contributing to inhibit the active site of oxi- dative catabolic enzymes cyclooxygenase (COX) and/or 5-lypooxygenase, which are responsible for the biosyn- thesis of prostaglandins, thromboxanes, and leukotri- enes. 2 The role of these autacoids in the genesis of several pathological states, including inflammation, pain, and asthma, are well known and decurrent from the over-expression of an induced isoform of COX, named COX-2. 3 In fact, selective COX-2 inhibitors comes being one of the most useful and successful classes of antiinflammatory drugs, due to its therapeu- tical safety and efficacy. 4 On the other hand, the action of certain heterocyclic hydrazone 5 and acylhydrazone 6 derivatives on blood platelets avoid platelet aggregation phenomena induced by (1) probably due to the inhibi- tion of COX-1 and the consequent reduction of the bioformation of thromboxane A 2 , as showed by pyrazol- yl-4-acylhydrazone derivative (3) (IC 50 ¼ 23.7 lM). 7 In spite of the discovery of that two isoforms of COX, the mechanism of action of classical analgesics and Figure 1. Hydrazone (B) and acylhydrazone (C) groups as mimicks of bis-allyl fragment (A) of arachidonic acid (1). Keywords: 10H-phenothiazine; Acylhydrazone derivatives; Analgesic activity; Antiplatelet drugs; Molecular hybridization. * Corresponding author. Tel.: +55-21-22609192; fax: +55-21-256266- 44; e-mail: cmfraga@pharma.ufrj.br URL: http://www.farmacia.ufrj.br/lassbio z In memoriam. 0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2004.04.009 Bioorganic & Medicinal Chemistry 12 (2004) 3149–3158