Antiedematogenic Activity of Two Thiazolidine Derivatives: N-Tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) Rhodanine (GS26) and N-Tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28)

Abstract

The main limitation in the use of anti-inflammatory drugs or drugs that inhibit some aspects of inflammation is their secondary effects, especially on the gastro-intestinal tract, during chronic use. Therefore, anti-inflammatory drugs without such effects have been one of the main objectives of researchers. 1)Modern organic chemistry development has provided an increased number of substances for various therapeutic aims. Among the methods for obtaining new drugs, molecular modification or variation using the Bioisostery concept is often used. Using this chemical concept, substitute groups can be introduced in one or more positions of a main molecule, creating similar compounds with varied biological activities that can show interesting medical properties. With this process, we can analyze the influence of the modification of an atom or a group of atoms on the main molecule's biological activity. The molecular alterations can result in molecules with similar, antagonistic or more larger potent activity than that of the original compound.2)The thiazolidinic and imidazolidinic nuclei represent a category of compounds that present promising biological activities: insecticidal, 3) antimicrobial, antifungal, narcotic, sedative, anesthetic, anticonvulsive and nematocidal. 4) Góes et al. (1991) 5) showed that thiazolidine and imidazolidine derivatives (or isosters) possess antifungal (against Candida albicans and Neurospora crassa) and moderate antibiotic activity (against E. coli, S. aureus and others).Among the compounds that possess a thiazolidinic nucleus, 2,4-thiazolidinedione ( Fig. 1) and rhodanine (Fig. 2) were studied by Lima (1999) 6) with respect to the antiedematogenic properties of their isosters. In this study antiedematogenic activity was found for two bioisosters, N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) (MWϭ476) (Fig. 3) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26) (MWϭ492) (Fig. 4). Studies related to acute toxicity (LD 50 ) of GS26 and GS28 in a range of oral doses of 25, 50, 100, 250, 500 and 1000 mg/kg did not indicate any toxicity. The aim of this study was to determine the existence of antiedematogenic properties on thiazolidinic isosters GS26 and GS28 in the response evoked by well-known edematogenic agents. Chemistry Two new compounds N-tryptophyl-5-(3,5-di-

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

“…Chemical structure of darbufelon has been considered as leadcompound for novel anti-inflammatory agents design till now. Optimization of the latter and application of the bioisostere concept allowed the elaboration of new bioactive compounds 138 (GS26) and 139 (GS28) (Scheme 71) with significant anti-inflammatory activity as well as antiedematogenic and ulcerogenic activity in vivo [363]. Further studies of related compounds allowed identifying selective inhibitors of COX-2 as promising anti-inflammatory agents with fewer side effects.…”

“…The row of hybrids 138 [363] (Scheme 71), 150 [375], 151 [376] (Scheme 77) based on indometacine, roziglitazone and darbufelone molecules was designed. The molecules possesed in vivo antiinflammatory activity in air pouch and peritonitis models or carrageenan induced paw edema model and inhibited the cyclooxygenase-1 and 2.…”

Diacetoxyiodobenzene mediated oxidative dethionation of N-substituted-5-arylmethylidene rhodanines: an efficient synthesis of N-substituted-5-arylmethylidene thiazolidine-2,4-diones

“…Silica gel (60−120 mesh size) was used for the column chromatography. 1 H NMR spectra were recorded on 400/600 MHz in CDCl3 and 13 C NMR spectra were recorded on 100/150 MHz in CDCl3 using TMS as internal standard. High-resolution mass spectral analysis (HRMS) data were recorded using ESI mode (Q-TOF type Mass Analyzer).…”

“…Thiazolidine-2,4-diones are important five membered N,S-heterocycles, which serve as the core components of numerous compounds that have been claimed to possess a wide range of interesting biological activities such as anti-inflammatory, 1 antidiabetic, 2 antimicrobial, 3 antimalarial, 4 and anticancer. 5 They are building blocks of many commercially available drugs such as troglitazone, pioglitazone, and rosiglitazone.…”

Preclinical pharmacokinetic and pharmacodynamic evaluation of thiazolidinone PG15: an anti-inflammatory candidate

“…This compound, that has an indol group attached to the thiazolidine central ring, was docked in the COX‐2 channel using the FlexX program interfaced with Sybyl 7.2 5 with good bonding, exhibiting a free energy of −13 254 kcal/mol. Silva and co‐workers (2003) 6 synthesized N ‐tryptophyl‐5‐(3,5‐di‐ tert ‐butyl‐4‐hydroxybenzylidene)‐2,4‐thiazolidinedione (Figure 1d), which, against carrageenan‐induced paw oedema, exhibited an average inhibition of 28.36% after a 100 mg/kg oral dose and did not show ulcerogenic activity on the gastric mucosa.…”