In silico Study of New Five-Membered Heterocyclic Derivatives Bearing (1,3,4-oxadiazole and 1,3,4-thiadiazole) As Promising Cyclooxygenase Inhibitors
DOI:
https://doi.org/10.32947/ajps.v24i3.1060Keywords:
Cambridge Crystallographic Data Center, Lipinski Rule, Molecular Docking, NabumetoneAbstract
A novel series of pyrazole, oxadiazole and thiadiazole bearing Nabumetone moiety were designed, synthesized, and evaluated for their anti-inflammatory activity against cyclooxygenase enzyme 2, after Insilico assay (by molecular docking study) a best set has been synthesized and characterized. After prediction of their activity by molecular docking study using Cambridge Crystallographic Data Base software tool (GOLD), We tested them in real in vivo as anti-inflammatory agents using egg white procedure. Due to their hydrogen bonding interaction with crucial amino acids in COX-2 isozymes Arg120, Tyr355, and Ser530, all tested compounds in molecular docking demonstrated significant activities compared with diclofenac, naproxen, and 6MNA as reference drugs. The data obtained from docking studies were highly correlated with that obtained from the in vivo assay in which compounds 3c, 6c, and 7c showed the best docking PLP fitness which were 91.35, 89.66, and 92.09 respectively with COX-2. Other compounds 2c, 4c, 5c, 6a, 6b, showed a PLP fitness above 80. The aim of this investigation was to produce novel NSAIDs, based on Nabumetone, that exhibit little or no gastro-toxicity and higher selectivity. This research offered helpful direction for the identification of novel pyrazole and thiadiazole anti-inflammatory compounds.
References
- Sabe VT, Ntombela T, Jhamba LA, Maguire GE, Govender T, Naicker T, Kruger HG. Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: A review. European Journal of Medicinal Chemistry. 2021 Nov 15; 224:113705. DOI: https://doi.org/10.1016/j.ejmech.2021.113705
- Palaska E, Şahin G, Kelicen P, Durlu NT, Altinok G. Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1, 3, 4-oxadiazoles, 1, 3, 4-thiadiazoles and 1, 2, 4-triazole-3-thiones. Il Farmaco. 2002 Feb 1;57(2):101-7. DOI: https://doi.org/10.1016/S0014-827X(01)01176-4
- Upadhyay A, Amanullah A, Joshi V, Dhiman R, Prajapati VK, Poluri KM, Mishra A. Ibuprofen-based advanced therapeutics: Breaking the inflammatory link in cancer, neurodegeneration, and diseases. Drug Metabolism Reviews. 2021 Jan 2;53(1):100-21. DOI: https://doi.org/10.1080/03602532.2021.1903488
- Majhi S, Saha I. Visible Light-promoted Synthesis of Bioactive N, N-heterocycles. Current Green Chemistry. 2022 Dec 1;9(3):127-44. DOI: https://doi.org/10.2174/2213346110666221223141323
- Desai KR, Patel BR. Various Synthetic Strategies and Therapeutic Potential of Thiadiazole, Oxadiazole, Isoxazole and Isothiazole Derivatives. InN-Heterocycles: Synthesis and Biological Evaluation 2022 Apr 24 (pp. 221-274). Singapore: Springer Nature Singapore. DOI: https://doi.org/10.1007/978-981-19-0832-3_6
- Ferrer MD, Busquets-Cortés C, Capó X, Tejada S, Tur JA, Pons A, Sureda A. Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases. Current medicinal chemistry. 2019 Jun 1;26(18):3225-41. DOI: https://doi.org/10.2174/0929867325666180514112124
- Fitzpatrick, F. A., & Wynalda, M. A. (1990). Albumin-catalyzed metabolism of prostaglandin D2. Identification of products formed in vitro. Journal of Biological Chemistry, 265(19), 10937-10940.
- Allawi MM, Mahdi MF, Raauf AM. Synthesis, anti-inflammatory, molecular docking and ADME studies of new derivatives of ketoprofen as cyclooxygenases inhibitor. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2019 Dec 1;19(4):125-39. DOI: https://doi.org/10.32947/ajps.v19i4.644
- Eddershaw, P. J., & Beresford, A. P. (2001). Design of selective COX-2 inhibitors: a journey into the structure-activity relationships of a class of anti-inflammatory drugs. Current Pharmaceutical Design, 7(15), 1509-1531.
- Chandrasekhar, S., & Madhusudhan, G. (2016). Strategies and recent advances in the discovery of selective cyclooxygenase-2 inhibitors. Future Medicinal Chemistry, 8(5), 569-585.
- Pinzi L, Rastelli G. Molecular docking: shifting paradigms in drug discovery. International journal of molecular sciences. 2019 Sep 4;20(18):4331. DOI: https://doi.org/10.3390/ijms20184331
- Eren G, Macchiarulo A, Banoglu E. From Molecular Docking to 3D‐Quantitative Structure‐Activity Relationships (3D‐QSAR): Insights into the Binding Mode of 5‐Lipoxygenase Inhibitors. Molecular Informatics. 2012 Feb;31(2):123-34. DOI: https://doi.org/10.1002/minf.201100101
- Jameel BK, Raauf AM, Abbas WA. Synthesis, characterization, molecular docking, in silico ADME study, and in vitro cytotoxicity evaluation of new pyridine derivatives of nabumetone. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2023 Jul 20;23(3):250-62. DOI: https://doi.org/10.32947/ajps.v23i3.1042
- Smith, M. B.; March, J. In March’s “Advanced Organic Chemistry, Reactions, Mechanisms, and Structure”, 5th ed.; Wiley-Interscience: New York; 2001.
- Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports. 2017 Mar 3; 7:42717. DOI: https://doi.org/10.1038/srep42717
- Daina A, Zoete V. A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem. 2016 Jun 6;11(11):1117-21 DOI: https://doi.org/10.1002/cmdc.201600182
- Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. Journal of molecular biology. 1997 Apr 4;267(3):727-48. DOI: https://doi.org/10.1006/jmbi.1996.0897
- Jones G, Willett P, Glen RC. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. Journal of molecular biology. 1995 Jan 1;245(1):43-53. DOI: https://doi.org/10.1016/S0022-2836(95)80037-9
- Webb EF, Griswold DE. Microprocessor-assisted plethysmograph for the measurment of mouse paw volume. Journal of pharmacological methods. 1984 Sep 1;12(2):149-53. DOI: https://doi.org/10.1016/0160-5402(84)90032-9
- Adeniyi AA, Ajibade PA. Comparing the suitability of autodock, gold and glide for the docking and predicting the possible targets of Ru (II)-based complexes as anticancer agents. Molecules. 2013 Mar 25;18(4):3760-78. DOI: https://doi.org/10.3390/molecules18043760
- Patrick GL. An introduction to medicinal chemistry. 1st ed. Oxford university press; 1995, p.31.
- Windsor MA, Hermanson DJ, Kingsley PJ, Xu S, Crews BC, Ho W, Keenan CM, Banerjee S, Sharkey KA, Marnett LJ. Substrate-selective inhibition of cyclooxygenase-2: development and evaluation of achiral profen probes. ACS medicinal chemistry letters. 2012 Aug 15;3(9):759-63. DOI: https://doi.org/10.1021/ml3001616
- Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, Banerjee S, Oates JA, Marnett LJ. (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nature chemical biology. 2011 Nov;7(11):803. DOI: https://doi.org/10.1038/nchembio.663
- Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996 Dec;384(6610):644. DOI: https://doi.org/10.1038/384644a0
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