Synthesis and Analgesic Activity of 2-Phenoxybenzoic Acid and N-Phenylanthranilic Acid Hydrazides

Abstract

Non steroidal anti-inflammatory drugs (NSAID's) are first line therapeutic agents for the treatment of arthritis. NSAID's reduce the pain and swelling associated with arthritis by blocking the metabolism of arachidonic acid (AA) through the enzyme cyclooxygenase (COX) and thereby the production of prostaglandins, e.g. PGE 2 , which sensitizes nociceptors at nerve fiber terminals. 1,2) Additionally, the 5-lipoxygenase (5-LO) products such as leukotriene B 4 (LTB 4 ) also contributes to the hyperalgesia seen during inflammation by decreasing the mechanical and thermal thresholds of C fiberes.3) Leukotrienes, especially LTB 4 together with prostaglandins are implicated in the acute ulceration induced by NSAID's. 4) For these reasons, compounds that achieve dual inhibition of enzymes COX and 5-LO reduce side effects and improved efficacy in the combat of pain in inflammatory diseases.5) Some evidences suggest that the hydrazone moiety present in phenylhydrazone derivative 1 (Fig. 1), possesses a pharmacophoric character for the inhibition of COX and hydrazone type containing compounds such as compound 2 (Fig. 1) were described as dual COX/5-LO inhibitors.6,7) According to these evidences, there are some reports about synthesis and pharmacological evaluation of new bioactive compounds with N-aroylarylhydrazone structure acting at the AA cascade enzyme level (Fig. 2, compounds 3-5). [8][9][10] On the basis of these reports, we described previously the synthesis and analgesic profile of Narylhydrazone derivatives of mefenamic acid 6 (Fig. 3), a known NSAID drug with fenamate structure.11) Most of these synthesized compounds were effective as analgesic agents in comparison to control and showed more analgesic activity in comparison to mefenamic acid. In fact, compound 7 (Fig. 3) displayed 3.6-fold greater potency than mefenamic acid as an analgesic agent, in a model of abdominal constrictions induced by acetic acid. These results led us to design new structurally related derivatives 10, 11. Target compounds 10, 11 were obtained according to Chart 1. The starting hydrazides 8 (XϭO, RϭH and XϭNH, RϭH) were prepared by the known procedures and hydrazide 8 (XϭO, RϭCl) was synthesized as described previously.12-17) Compounds 10, 11 were synthesized by acid-catalyzed condensation of hydrazides 8 with corresponding substituted benzaldehydes or acetophenones.10,11) The synthesis and antimicrobial activity A series of 2-phenoxybenzoic acid and N-phenylanthranilic acid hydrazides were synthesized and evaluated for their analgesic activities. Several compounds were significantly more potent than mefenamic acid and diclofenac sodium in abdominal constriction and formalin tests.

Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor α Production

“…Thus, the compounds described here are unique in their ability to activate this response via a GPCR. On the other hand, compounds with this scaffold have been reported among agents with antitumor (Boykin and Varma, 1970), proapoptotic (Zhang et al, 2004), antiprion (Bertsch et al, 2005), analgesic (Almasirad et al, 2006), and antioxidant (Simunek et al, 2005) properties. Hence, our findings suggest the possibility that the antitumor and proapoptotic effects reported for arylcarboxylic acid hydrazides could be due, in part, to activation of TNF-␣ production.…”

Synthesis and analgesic activity of new 1,3,4-oxadiazoles and 1,2,4-triazoles

“…As a part of our ongoing research program to find novel anti-inflammatory, analgesic, and anticonvulsant compounds, herein, we describe the synthesis and analgesic activity of new analogues of compound 2 by bioisosteric replacement of NH with S and oxidation of S to SO and SO 2 in order to make this moiety as a real hydrogen bond acceptor similar to NH in compound 2 and in the hope of obtaining additional inhibitors of AA metabolism (Almasirad et al, 2005;Almasirad et al, 2006;Rineh et al, 2007;Shafiee et al, 2009).…”

Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities

“…2-Benzylidene-1-phenylhydrazine derivative (6) has been proposed as a COX-2 inhibitor and hydrazine derivative (7) is described as a dual COX/5-LOX inhibitor 31 . With respect to these structural features, we designed a set of COX-2 inhibitors.…”