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

Figures & data

Scheme 1.  Retroanalysis of Darbufelone (CI1004), a dual COX/LOX inhibitor. Pharmacophore generated from structure analysis of Darbufelone.

Scheme 2.  Probable mechanism of metabolic toxicity exhibited by Romazarit. Peroxy type radicals or methyl acrylic acid moiety might be responsible for the bladder tumor formation.

Scheme 3.  Synthetic route for the different 4-benzyl-1,3-thiazole derivatives 5-16.

Scheme 4.  Probable metabolic pathways of most potent compound RS31. The bioisosteric replacement of CH₂ group at second position by NH obstructs the pathway that may generate peroxy type radicals or methyl acrylic acid moiety.

Figure 1.  Dose response curves of two randomly chosen compounds RS11 and RS31.

Table I.  In vivo anti-inflammatory activity data of the 4-benzyl-1,3-thiazol derivatives.

Compound	Candidate Code	R1	R2	Anti-inflammatory activity [% Protection ± S.E.M] After 3 h
5	RS11		OCH3	55.8 ± 1.21*
6	RS12		H	12.9 ± 3.65**
7	RS13		Cl	44.2 ± 1.89*
8	RS21		OCH3	35.3 ± 2.53**
9	RS22		H	18.4 ± 3.23**
10	RS23		Cl	42.4 ± 2.21*
11	RS31		OCH3	60.8 ± 1.45*
12	RS32		H	36.2 ± 2.13**
13	RS33		Cl	44.4 ± 2.43*
14	RS41		OCH3	52.6 ± 1.56*
15	RS42		H	30.1 ± 2.45**
16	RS43		Cl	45.6 ± 2.31*
Standard 1	Ibuprofen			60.1 ± 1.75*
Standard 2	Rofecoxib			43.6 ± 1.23*
Standard 3	Caffeic acid			11.2 ± 2.03**
Standard 4	NDGA			21.8 ± 1.13*

The test drugs were dosed at 50 mg/kg body weight po. Ibuprofen was dosed at 100 mg/kg body weight po. Rofecoxib, Caffeic acid and NDGA were dosed at 50 mg/kg body weight po. *Significant difference at P < 0.001, ** Significant difference at P < 0.05.

Figure 2.  Proposed three point pharmacophore for designing dual acting anti-inflammatory agents.

Figure 3.  Superimposition analysis of most active molecule RS31 (a) with Darbufelone (b) with Romazarit.