Bioorganic Chemistry p. 393 - 400 (2019)
Update date:2022-08-16
Topics:
Atatreh, Noor
Youssef, Amal M.
Ghattas, Mohammad A.
Al Sorkhy, Mohammad
Alrawashdeh, Sara
Al-Harbi, Khaled B.
El-Ashmawy, Ibrahim M.
Almundarij, Tariq I.
Abdelghani, Amani A.
Abd-El-Aziz, Alaa S.
In this study, the acid chlorides of pyrazolo[3,4-d]pyrimidine compounds were prepared and reacted with a number of nucleophiles. The novel compounds were experimentally tested via enzyme assay and they showed cyclooxygenase-2 inhibition activity in the middle micro molar range (4b had a COX-1 IC50 of 26 μM and a COX-2 IC50 of 34 μM, 3b had a COX-1 IC50 of 19 μM and a COX-2 IC50 of 31 μM, 3a had a COX-2 IC50 of 42 μM). These compounds were analyzed via docking and were predicted to interact with some of the COX-2 key residues. Our best hit, 4d (COX-1 IC50 of 28 μM, COX-2 IC50 of 23 μM), appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. Additionally, the resultant novel compounds were tested in several in vivo assays. Four compounds 3a (COX-2 IC50 of 42 μM), 3d, 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available COX-2 inhibitor celecoxib. Interestingly, they showed greater potency than the famous non-steroidal anti-inflammatory drug, Diclofenac sodium. In summary, these novel pyrazolo[3,4-d]pyrimidine analogues showed interesting anti-inflammatory activity and could act as a starting point for future drugs.
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