Synthesis, X-ray Crystallography, and Computational Analysis of 2,4-disubstituted-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidines as COX-2 Inhibitors and Anticancer Agents

Abstract

A series of fourteen 2,4-disubstituted-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine derivatives (5-18) were synthesized, characterized, and tested (in vitro) for their affinity and selectivity for the human cyclooxygenase 2 (COX-2) enzyme against the COX-1 isoenzyme. Compounds 9, 12, 14, and 17 showed good selectivity for COX-2 against COX-1. Compounds 5-18 were also evaluated for their cytotoxicity against breast cancer, ovarian cancer, and cervical cancer cell lines. Compound 6 was found to be the most selective, with very high cytotoxicity (85%) against cervical cancer cells as compared to doxorubicin (45%). Moreover, a computational study was conducted to study the binding modes of these compounds to explain the observed selectivity. The docking and MD simulations studies revealed that the achieved selectivity for COX-2 isoenzyme is attributed to the larger size of its allosteric pocket. In conclusion, these compounds can be considered as lead molecules that could be further optimized to discover novel potent and selective COX-2 inhibitors with anticancer properties.