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Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents.
Medchemcomm 2019; 10(10):1775-1788M

Abstract

Herein, the design and synthesis of some novel 1,3,4-trisubstituted pyrazole derivatives was carried out through the structural modification of lonazolac. All the synthesized compounds were investigated for in vitro COX-1 & COX-2 inhibition and in vivo anti-inflammatory activity by a carrageenan rat paw edema model. Among them, the chalcones 2a and 2b were the most COX-2 selective derivatives (S.I. = 8.22 and 9.31, respectively) and revealed very good in vivo anti-inflammatory potency. Similarly, the compounds 4a, 6b, 7a and 8a exhibited good COX-2 selectivity and in vivo anti-inflammatory activity. The active compounds were selected to further investigate their ulcerogenic activity, and they were found to be less ulcerogenic (ulcer indices = 2.4-8.4) as compared to indomethacin (ulcer index = 17.6) and nearly as ulcerogenic as celecoxib (ulcer index = 8.1). Moreover, histological studies were performed to evaluate the safety of these compounds on the stomach, liver and kidney. Furthermore, a docking study was performed to determine possible binding of the most active compounds 2a and 2b, which showed high docking scores (-9.461 and -7.962 kcal mol-1, respectively) that were comparable to that of celecoxib (-8.692 kcal mol-1).

Authors+Show Affiliations

Department of Pharmaceutical Chemistry , Faculty of Pharmacy (Girls) , Al-Azhar University , Cairo , Egypt.Department of Pharmaceutical Chemistry , Faculty of Pharmacy (Girls) , Al-Azhar University , Cairo , Egypt.Department of Pharmaceutical Sciences , College of Pharmacy , Princess Nourah bint Abdulrahman University , Riyadh , Kingdom of Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31803395

Citation

Harras, Marwa F., et al. "Discovery of New Non-acidic Lonazolac Analogues With COX-2 Selectivity as Potent Anti-inflammatory Agents." MedChemComm, vol. 10, no. 10, 2019, pp. 1775-1788.
Harras MF, Sabour R, Alkamali OM. Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents. Medchemcomm. 2019;10(10):1775-1788.
Harras, M. F., Sabour, R., & Alkamali, O. M. (2019). Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents. MedChemComm, 10(10), pp. 1775-1788. doi:10.1039/c9md00228f.
Harras MF, Sabour R, Alkamali OM. Discovery of New Non-acidic Lonazolac Analogues With COX-2 Selectivity as Potent Anti-inflammatory Agents. Medchemcomm. 2019 Oct 1;10(10):1775-1788. PubMed PMID: 31803395.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents. AU - Harras,Marwa F, AU - Sabour,Rehab, AU - Alkamali,Omkulthom Mohamed, Y1 - 2019/07/22/ PY - 2019/04/17/received PY - 2019/07/17/accepted PY - 2020/07/22/pmc-release PY - 2019/12/6/entrez PY - 2019/12/6/pubmed PY - 2019/12/6/medline SP - 1775 EP - 1788 JF - MedChemComm JO - Medchemcomm VL - 10 IS - 10 N2 - Herein, the design and synthesis of some novel 1,3,4-trisubstituted pyrazole derivatives was carried out through the structural modification of lonazolac. All the synthesized compounds were investigated for in vitro COX-1 & COX-2 inhibition and in vivo anti-inflammatory activity by a carrageenan rat paw edema model. Among them, the chalcones 2a and 2b were the most COX-2 selective derivatives (S.I. = 8.22 and 9.31, respectively) and revealed very good in vivo anti-inflammatory potency. Similarly, the compounds 4a, 6b, 7a and 8a exhibited good COX-2 selectivity and in vivo anti-inflammatory activity. The active compounds were selected to further investigate their ulcerogenic activity, and they were found to be less ulcerogenic (ulcer indices = 2.4-8.4) as compared to indomethacin (ulcer index = 17.6) and nearly as ulcerogenic as celecoxib (ulcer index = 8.1). Moreover, histological studies were performed to evaluate the safety of these compounds on the stomach, liver and kidney. Furthermore, a docking study was performed to determine possible binding of the most active compounds 2a and 2b, which showed high docking scores (-9.461 and -7.962 kcal mol-1, respectively) that were comparable to that of celecoxib (-8.692 kcal mol-1). SN - 2040-2511 UR - https://www.unboundmedicine.com/medline/citation/31803395/Discovery_of_new_non-acidic_lonazolac_analogues_with_COX-2_selectivity_as_potent_anti-inflammatory_agents L2 - https://doi.org/10.1039/c9md00228f DB - PRIME DP - Unbound Medicine ER -