Synthesis of 4-benzyl-1,3-thiazole derivatives as potential anti-inflammatory agents: An analogue-based drug design approach

Abstract

A series of novel 4-Benzyl-1,3-thiazole derivatives was synthesized by applying analogue-based drug design approach and they were screened for anti-inflammatory activity. Darbufelone (CI 1004) a dual COX/LOX inhibitor, served as a lead molecule for designing a molecular scaffold. The derivatives with the 1,3 thiazole molecular scaffold bearing a side chain at position-2 resembling that of Romazarit (Ro-31-3948) were synthesized. The substitution at the second position of thiazole scaffold consisted of either carbalkoxy amino or aryl amino side chain. The introduction of an NH linker at the second position was the bioisoteric approach to impart the metabolic stability to the carbalkoxy side chains in designed molecules so as to avoid the likelihood of generating toxic moieties, like in Romazarit, which was withdrawn due to its toxicity profile. An important outcome of this study is the optimization of the substitution at the second position of the thiazole scaffold in eliciting better biological activity. The biological activity exhibited by the two designed series were in the order of carbalkoxy amino series . phenyl amino series. Molecule RS31 had emerged to be best compound in the whole series, having the side chain -NH-(CvO)O-R which resemble to Romazerit with 1,3 thiazole scaffold and substituted phenyl carbonyl group at fifth position derived from the retro-analysis of Darbufelone. This novel three-point pharmacophore, which is necessarily evolved from a lead-based drug design strategy, has opened up new avenues in designing of molecules acting on more than one rate-limiting step along the inflammatory cascade.

Reaction of N,N-disubstituted hydrazinecarbothioamides with 2-bromo-2-substituted acetophenones

“…Free radicals and reactive sulfur species such as thiol radicals are frequently synthesized through many biological processes and may be considered as indicators of biological inadequacy. In recent times, the applications of thiazoles have found in drug development for the treatment of allergies 6 , hypertension, 7 inflammation, 8 schizophrenia, 9 bacterial, 10 HIV infections, 11 and hypnotics 12 . Moreover, thiazoles have been used for the treatment of pain, 13 as fibrinogen receptor antagonists with antithrombotic activity 14 and as new inhibitors of bacterial DNA gyrase B.…”

Thiazoles: having diverse biological activities

“…It has been observed over the years that thiazole derivatives have several biological activities such as antihypertensive activity (Patt et al, 1992), anti-inflammatory activity (Sharma et al, 2009), antischizophrenia activity (Jaen et al, 1990), antibacterial activity (Tsuji and Ishikawa, 1994), anti-HIV activity (Bell et al, 1995), hypnotics activity (Ergenc et al, 1999), antiallergic activity (Hargrave et al, 1983), analgesic activity (Carter et al, 1999), fibrinogen receptor antagonist activity with antithrombotic activity (Badorc et al, 1997), as bacterial DNA gyrase B inhibitor activity (Rudolph et al, 2001), antitumor and cytotoxic activity (Gulsory and Guzeldemirci 2007).…”

A Thiazole Analogue Exhibits an Anti-Proliferative Effect in Different Human Carcinoma Cell Lines and Its Mechanism Based on Molecular Modeling

“…In tumor cells, several observations suggesting that ROS may mediate apoptosis, thus depletion of endogenous antioxidants can promote apoptosis, and presence of endogenous antioxidants can sometimes delay or inhibit apoptosis [17] suggesting that the use of anti-SOD may be of significance as an anti-cancer drug [18].…”