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chains in designed molecules so as to avoid the likelihood of generating toxic moieties, like in Romazarit, which was withdrawn due to its toxicity profile.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-(C=O)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.