A Novel Series of Pyrazole and Thiadiazole Derivatives Bearing Nabumetone Moiety: Design, Molecular Docking Study, Synthesis, Characterization, and Preliminary Pharmacological Evaluation
DOI:
https://doi.org/10.31351/vol34iss1pp85-95Abstract
A series of new pyrazole and thiadiazole compounds including the Nabumetone moiety were conceptualized, produced, and subjected to assessment for their anti-inflammatory potential against cyclooxygenase enzyme 2. Following an Insilico test involving molecular docking analysis, the most promising compound set was synthesized and further described. 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. Hydrogen bonding interaction with key amino acids in COX-2 isozymes, including Arginine120, Tyrosine355, and Serine530, gave the compounds investigated in molecular docking much higher activity than the reference drugs naproxen, diclofenac, and 6MNA. The data obtained from docking studies were highly correlated with that obtained from the in vivo assay. Compounds 3c, 4c, 5c showed a PLP fitness 91.35, 89.66 and 92.09 respectively, which are the best scores from all synthesized compounds. This research offered helpful direction for the identification of novel pyrazole and thiadiazole anti-inflammatory compounds.
How to Cite
Publication Dates
Received
Revised
Accepted
Published Online First
References
Szandruk-Bender M, Merwid-Ląd A, Wiatrak B, Danielewski M, Dzimira S, Szkudlarek D, Szczukowski Ł, Świątek P, Szeląg A. Novel 1, 3, 4-oxadiazole derivatives of pyrrolo [3, 4-d] pyridazinone exert anti-inflammatory activity without acute gastrotoxicity in the carrageenan-induced rat paw edema test. Journal of Inflammation Research. 2021;14:5739.
Tziona P, Theodosis-Nobelos P, Papagiouvannis G, Petrou A, Drouza C, Rekka EA. Enhancement of the anti-inflammatory activity of NSAIDs by their conjugation with 3, 4, 5-trimethoxybenzyl alcohol. Molecules. 2022 Mar 24;27(7):2104.
Osmaniye D, Sağlık BN, Levent S, Özkay Y, Kaplancıklı ZA. Design, synthesis and biological evaluation of new N‐acyl hydrazones with a methyl sulfonyl moiety as selective COX‐2 inhibitors. Chemistry & Biodiversity. 2021 Nov;18(11):e2100521.
Cui J, Jia J. Natural COX-2 inhibitors as promising anti-inflammatory agents: an update. Current Medicinal Chemistry. 2021 Jun 1;28(18):3622-46.
Venugopala KN, Chandrashekharappa S, Tratrat C, Deb PK, Nagdeve RD, Nayak SK, Morsy MA, Borah P, Mahomoodally FM, Mailavaram RP, Attimarad M. Crystallography, molecular modeling, and COX-2 inhibition studies on indolizine derivatives. Molecules. 2021 Jun 10;26(12):3550.
Cruz JV, Giuliatti S, Alves LB, Silva RC, Ferreira EF, Kimani NM, Silva CH, Souza JS, Espejo-Román JM, Santos CB. Identification of novel potential cyclooxygenase-2 inhibitors using ligand-and structure-based virtual screening approaches. Journal of Biomolecular Structure and Dynamics. 2022 Jul 14;40(12):5386-408.
Yousif OA, Mahdi MF, Raauf AM. Design, synthesis, preliminary pharmacological evaluation, molecular docking and ADME studies of some new pyrazoline, isoxazoline and pyrimidine derivatives bearing nabumetone moiety targeting cyclooxygenase enzyme. Journal of Contemporary Medical Sciences. 2019 Jan;5(1):41-50.
Ghanim AM, Girgis AS, Kariuki BM, Samir N, Said MF, Abdelnaser A, Nasr S, Bekheit MS, Abdelhameed MF, Almalki AJ, Ibrahim TS. Design and synthesis of ibuprofen-quinoline conjugates as potential anti-inflammatory and analgesic drug candidates. Bioorganic chemistry. 2022 Feb 1;119:105557.
Lodochnikova OA, Islamov DR, Gerasimova DP, Zakharychev DV, Saifina AF, Pestova SV, Izmest'ev ES, Rubtsova SA, Pavelyev RS, Rakhmatullin IZ, Klochkov VV. Isobornanyl sulfoxides and isobornanyl sulfone: Physicochemical characteristics and the features of crystal structure. Journal of Molecular Structure. 2021 Sep 5;1239:130491.
Zárate-Zárate D, Aguilar R, Hernández-Benitez RI, Labarrios EM, Delgado F, Tamariz J. Synthesis of α-ketols by functionalization of captodative alkenes and divergent preparation of heterocycles and natural products. Tetrahedron. 2015 Sep 23;71(38):6961-78.
Ansari A, Ali A, Asif M. Biologically active pyrazole derivatives. New Journal of Chemistry. 2017;41(1):16-41.
Ahmed M., Qadir MA., Hameed A., Imran M., Muddassar M. Screening of curcuminderived isoxazole, pyrazoles, and pyrimidines for their anti-inflammatory, antinociceptive, and cyclooxygenase-2 inhibition. Chem Biol Drug Des (2018) 91 338‐343.
Saha S, Pal D. Role of Pyrazole Ring in Neurological Drug Discovery. Pyrazole Preparartion and Uses. 2020:245-64.
Somakala K, Amir M. Synthesis, characterization and pharmacological evaluation of pyrazolyl urea derivatives as potential anti-inflammatory agents. Acta pharmaceutica sinica B. 2017 Mar 1;7(2):230-40.
El-Shoukrofy MS., Abd El Razik HA., AboulWafa OM., Bayad AE., El-Ashmawy IM. Pyrazoles containing thiophene, thienopyrimidine and thienotriazolopyrimidine as COX-2 selective inhibitors: Design, synthesis, in vivo anti-inflammatory activity, docking and in silico chemo-informatic studies. Bioorg Chem (2019) 85 541–57. https://doi.org/10.1016/j.bioorg.2019.02.036.
Ali SH, Sayed AR. Review of the synthesis and biological activity of thiazoles. Synthetic Communications. 2021 Mar 4;51(5):670-700.
Arshad MF, Alam A, Alshammari AA, Alhazza MB, Alzimam IM, Alam MA, Mustafa G, Ansari MS, Alotaibi AM, Alotaibi AA, Kumar S. Thiazole: A versatile standalone moiety contributing to the development of various drugs and biologically active agents. Molecules. 2022 Jun 21;27(13):3994.
Gurunanjappa P, Kariyappa A. Design, synthesis and biological evaluation of 1, 3, 4-oxadiazoles/thiadiazoles bearing pyrazole scaffold as antimicrobial and antioxidant candidates. Current Chemistry Letters. 2016;5(3):109-22.
KhanYusufzai S, Osman H, Khan MS, Mohamad S, Sulaiman O, Parumasivam T, Gansau JA, Johansah N. Design, characterization, in vitro antibacterial, antitubercular evaluation and structure-activity relationships of new hydrazinyl thiazolyl coumarin derivatives. Medicinal Chemistry Research.2017Junel;26(6):1139-1148.
Hassan M, Ghaffari R, Sardari S, Farahani YF, Mohebbi S. Discovery of novel isatin-based thiosemicarbazones: synthesis, antibacterial, antifungal, and antimycobacterial screening. Research in Pharmaceutical Sciences. 2020 Jun;15(3):281.
Uchiyama S, Inaba Y, Matsumoto M, Suzuki G. Reductive amination of aldehyde 2, 4-dinitorophenylhydrazones using 2-picoline borane and high-performance liquid chromatographic analysis. Analytical Chemistry. 2009 Jan 1;81(1):485-9.
Srivastava A, Singh RM. Vilsmeier-Haack reagent: a facile synthesis of 2-chloro-3-formylquinolines from N-arylacetamides and transformation into different functionalities.
Gurunanjappa P, Kariyappa A. Design, synthesis and biological evaluation of 1, 3, 4-oxadiazoles/thiadiazoles bearing pyrazole scaffold as antimicrobial and antioxidant candidates. Current Chemistry Letters. 2016;5(3):109-22.
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717.
Friedman HL. Influence of isosteric replacements upon biological activity. NAS-NRS Publication. 1951;206:295-358.
García-Ortegón M, Simm GN, Tripp AJ, Hernández-Lobato JM, Bender A, Bacallado S. DOCKSTRING: easy molecular docking yields better benchmarks for ligand design. Journal of chemical information and modeling. 2022 Jul 18;62(15):3486-502.
Stanzione F, Giangreco I, Cole JC. Use of molecular docking computational tools in drug discovery. Progress in Medicinal Chemistry. 2021 Jan 1;60:273-343.
Jakhar R, Dangi M, Khichi A, Chhillar AK. Relevance of molecular docking studies in drug designing. Current Bioinformatics. 2020 May 1;15(4):270-8.
Sulimov VB, Kutov DC, Sulimov AV. Advances in docking. Current medicinal chemistry. 2019 Dec 1;26(42):7555-80.
Kadhim YM, Lafta SJ, Mahdi MF. Synthesis in microwave, pharmacological evaluation, molecular docking and ADME studies of Schiff bases of Diclofenac targeting COX-2. vol.;11:88-101.
Robichaud A, Fereydoonzad L, Limjunyawong N, Rabold R, Allard B, Benedetti A, Martin JG, Mitzner W. Automated full-range pressure-volume curves in mice and rats. Journal of applied physiology. 2017 Oct 1;123(4):746-56.
Dahlgren D, Lennernäs H. Intestinal permeability and drug absorption: predictive experimental, computational and in vivo approaches. Pharmaceutics. 2019 Aug 13;11(8):411.
Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein–ligand docking using GOLD. Proteins: Structure, Function, and Bioinformatics. 2003 Sep;52(4):609-23.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Iraqi Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
