Background: Long term use of NSAIDS is mainly accompanied by major health implications
such as gastrointestinal erosions, ulcerations and nephrotoxicity. These side effects arise from local
irritation by the carboxylic acid moiety, that is common to most of NSAIDs (topical effect), in addition
to decreased cytoprotective prostaglandin production. Therefore, in the medicinal chemistry research
area, there is an ongoing need for the discovery of new, potent and safer anti-inflammatory lead
compounds devoid of the irritant carboxylic acid moiety.
Methods: A series of new 3-substituted-2-thioxo-thieno[2,3-d]pyrimidine derivatives were synthesized through reacting
the starting 3-amino-2-thioxo-thieno[2,3-d]pyrimidines with different aromatic aldehydes. The structure of all newly synthesized
compounds was confirmed with spectral and elemental analyses. The synthesized thieno[2,3-d]pyrimidines were
investigated for in vivo anti-inflammatory activity, using the carrageenan induced paw edema test. The possible antiinflammatory
mechanism was also evaluated by determining the concentration of prostaglandin E2 (PGE2) in blood serum
using a rat specific PGE2 ELISA kit.
Results: All test compounds could significantly reduce carrageenan induced paw edema comparable to diclofenac sodium
as a potent anti-inflammatory drug. Moreover, they could decrease the concentration of PGE2 in blood serum. Interestingly,
compound 4c exhibited the most potent in vivo anti-inflammatory activity with protection of 35%, 36% and 42%
against carrageenan-induced paw edema after 1h, 2h and 3h, representing 92%, 86% and 88% respectively of diclofenac
activity. It also decreased the concentration of PGE2 in blood serum to 19 pg/ mL which is comparable to diclofenac with
PGE2 concentration of 12 pg/ mL. Moreover, Compounds 4f, 4a, 4i and 4e exerted significant anti-inflammatory activity
after 4h, representing 71%, 69%, 63% and 61% respectively of diclofenac activity. Furthermore, they significantly decreased
the concentration of PGE2 in blood serum.
Conclusion: These thienopyrimidines may be used as good candidates for the search of promising, potent and safe antiinflammatory
leads for being free from acidic functions.