Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues.
This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues:5a-5u. Among the series5a-5u, the compounds5uand5sexhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected for assessment of their in vitro inhibitory action against COX1/2 and TNFα. The compounds5uand5sshowed high COX2-inhibitory activity, with half-maximal inhibitory concentrations of 1.79 and 2.51 μM and selectivity index values of 72.73 and 65.75, respectively, comparable to celecoxib (selectivity index =78.06). These selected compounds were also tested for TNFα, cytotoxicity, and ulcerogenicity. Docking studies were also carried out to determine possible interactions of the potent compounds (5uand5s), which also showed high docking scores of -12.907 and -12.24 compared to celecoxib, with a -9.924 docking score. These selective COX2 inhibitors were docked into the active site of COX2, and showed the same orientation and binding mode to that of celecoxib (selective COX2 inhibitor). Docking studies also showed that the SO2NH2of5uand5sis inserted deep inside the selective pocket of the COX2-active site and formed a hydrogen-bond interaction with His90, Arg513, Phe518, Ser353, Gln192, and Ile517, which was further validated by superimposed docked pose with celecoxib.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy.
Md Jahangir
MJ
Alam
Department of Pharmaceutical Chemistry, Faculty of Pharmacy.
Ozair
O
Alam
Department of Pharmaceutical Chemistry, Faculty of Pharmacy.
Suroor Ahmad
SA
Khan
Department of Pharmaceutical Chemistry, Faculty of Pharmacy.
Mohd Javed
MJ
Naim
Parasite Immunology Laboratory, Department of Biotechnology, Faculty of Science, Jamia Hamdard, New Delhi.
Mohammad
M
Islamuddin
Institute of Life Sciences, University of Hyderabad, Hyderabad, India.
Girdhar Singh
GS
Deora
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D051546:Cyclooxygenase 2; D007052:Ibuprofen
TNFα inhibition; analgesic activity; anti-inflammatory activity; molecular docking studies; pyrazole; selective COX2 inhibition