title: Novel pyrazolopyrimidine derivatives targeting COXs and iNOS enzymes; design, synthesis and biological evaluation as potential anti-inflammatory agents.
abstract: A novel set of 4-substituted-1-phenyl-pyrazolo[3,4-d]pyrimidine and 5-substituted-1-phenyl-pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized and evaluated as potential anti-inflammatory agents. The newly prepared compounds were assessed through the examination of their in vitro inhibition of four targets; cyclooxygenases subtypes (COX-1 and COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB). Compounds 8a, 10c and 13c were the most potent and selective ligands against COX-2 with inhibition percentages of 79.6%, 78.7% and 78.9% at a concentration of 2 μM respectively, while compound 13c significantly inhibited both COX subtypes. On the other hand, fourteen compounds showed high iNOS inhibitory activities with IC50 values in the range of 0.22-8.5μM where the urea derivative 11 was the most active compound with IC50 value of 0.22 μM. Most of the tested compounds were found to be devoid of inhibitory activity against NF-kB. Moreover, almost all compounds were not cytotoxic, (up to 25 μg/ml), against a panel of normal and cancer cell lines. The in silico docking results were in agreement with the in vitro inhibitory activities against COXs and iNOS enzymes. The results of in vivo anti-inflammatory and antinociceptive studies were consistent with that of in vitro studies which confirmed that compounds 8a, 10c and 13c have significant anti-inflammatory and analgesic activities comparable to that of the control, ketorolac. Taken together, dual inhibition of COXs and iNOS with novel pyrazolopyrimidine derivatives is a valid strategy for the development of anti-inflammatory/analgesic agents with the probability of fewer side effects.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Abdelazeem
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
authors.forename: Shaimaa A
authors.initials: SA
authors.lastname: Abdelatef
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
authors.forename: Mohammed T
authors.initials: MT
authors.lastname: El-Saadi
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
authors.forename: Hany A
authors.initials: HA
authors.lastname: Omar
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, MS 38677, USA.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, MS 38677, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: drsamirelmoghazy@yahoo.com.
authors.forename: Samir M
authors.initials: SM
authors.lastname: El-Moghazy
mesh_terms: D019342:Acetic Acid; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002351:Carrageenan; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D018374:LLC-PK1 Cells; D051379:Mice; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine; D014709:Vero Cells
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D011743:Pyrimidines; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019342:Acetic Acid
keywords: Analgesic; Anti-inflammatory; COX; NF-κB; Pyrazolopyrimidines; iNOS