A series of 17 novel tetra substituted
thiophenes was designed, synthesized, and screened for anti-inflammatory activity in
carrageenin induced rat paw
edema model, an acute in vivo model. The lead molecule selected was
Tenidap, a dual COX/LOX inhibitor. Compounds I (43%), III (60%), IV (60%), and VIII (64%) showed moderate to good anti-inflammatory activity. The best candidate among the whole series was VIII, which gave 64% protection to the inflamed paw. The side chain of candidate VIII had resemblance to that of
Romazarit, a
DMARD, which was withdrawn due to its toxicity profile. A probable reason for the metabolic stability of the proposed side chain not having the possibility of generating peroxy type radicals or
acrylic acid moieties, unlike
Romazarit, is discussed. The
biological activity exhibited by the three designed series was in the order of methyl amino series > ethyl amino series > carbethoxy amino series. The -(C=O)-CH2-COOR side chain at the fifth position as in candidate VIII, the methyl amino group at the second position, and the
ester at the third position of the
thiophene can be considered as a three-point pharmacophore for designing better
anti-inflammatory agents. The present study is a classical example of the exploitation of an analogue based
drug design, which culminated in the development of good
anti-inflammatory agents that have the potential of becoming dual inhibitors.