Anti-inflammatory drug approach: Synthesis and biological evaluation of novel pyrazolo[3,4-d]pyrimidine compounds

• Published in: Bioorganic chemistry Vol. 86; pp. 393 - 400
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2019
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-inflammatory drugs; Carrageenan; COX inhibitor; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Disease Models, Animal; Docking; Dose-Response Relationship, Drug; Edema - chemically induced; Edema - drug therapy; Granuloma - chemically induced; Granuloma - drug therapy; Humans; Inflammation - chemically induced; Inflammation - drug therapy; Male; Molecular Docking Simulation; Molecular Structure; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazolo[3,4-d]pyrimidines; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Rats, Wistar; Recombinant Proteins - metabolism; Structure-Activity Relationship; Synthesis; Turpentine; COX inhibitor; Docking; Synthesis; Anti-inflammatory drugs; Pyrazolo[3,4-d]pyrimidines
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.02.014

The present work describes the design and synthesis of novel series of ten pyrazolo[3,4-d]pyrazolo derivatives. Four compounds 3a, 3d, 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available cyclooxygenase-2 inhibitor celecoxib. They are even more potent than non-sterodial anti-inflammatory drug cyclooxygenase inhibitor diclofenac sodium. Our best hit 4d appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. The in silico findings come in line with the in vitro and in vivo assay results and also suggest that these compounds have the potetntial to be COX-2 selective inhibitors since they have typical binding modes of the benchmark drug celecoxib.
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•Design and synthesis of novel series of pyrazolo[3,4-d]pyrazolo derivatives.•The best hit, 4d with COX-1 IC50 of 28 µM and COX-2 IC50 of 23 µM.•4d adopt similar binding modes to the standard COX-2 inhibitor, celecoxib.•3a, 3d, 4d and 4f exhibited anti-inflammatory activity that was comparable to celecoxib.
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.