1,4-Dihydroquinazolin-3(2H)-yl benzamide derivatives as anti-inflammatory and analgesic agents with an improved gastric profile: Design,synthesis, COX-1/2 inhibitory activity and molecular docking study |
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| Affiliation: | 1. West Chester University, West Chester, PA, United States;2. Michigan State University, East Lansing, MI, United States;1. Department of Pharmaceutical Chemistry, Dr. Rajendra Gode College of Pharmacy, Malkapur, MS, 443101, India;2. Department of Pharmacology, Shri R. D. Bhakt College of Pharmacy, Jalna, Maharashtra, 431203, India;3. Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, MS, India;4. Department of Pharmaceutical Chemistry, H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, MS, India;1. Department of Chemistry, Faculty of Science, The Hashemite University, P. O. Box 330127, Zarqa 13133, Jordan;2. Department of Biology and Biotechnology, Faculty of Science, American University of Madaba, P.O. Box: 99, Madaba 17110, Jordan;3. Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada;4. Department of Biology and Chemistry, College of Arts and Sciences, Embry-Riddle Aeronautical University, 3700 Willow Creek Rd, Prescott, AZ 86301, USA;5. College of Engineering, Advanced Computing Simulations Laboratory, Prescott, AZ 86301, USA;6. Department of Physics, The University of Jordan, Amman, Jordan;7. Department of Biology and Chemistry, Tabor College, Hillsboro, KS 67063, USA |
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| Abstract: | The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a–o) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors are reported. The target compounds (4a–o) were synthesized using a two-step scheme, and their chemical structures were confirmed with 1H NMR, 13C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC50 0.04–0.07 μM), which was nearly the same as that of the reference drug celecoxib (IC50 0.049 μM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates. |
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| Keywords: | COX-1/2 inhibition Dihydroquinazolinyl benzamide Inflammation Molecular modeling |
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