Synthesis, Characterization and Preliminary Pharmacological Evaluation of New Naproxen Containing 1,3,4-thiadiazole-2-thiol Derivatives
DOI:
https://doi.org/10.31351/vol33iss(4SI)pp349-361Keywords:
nonsteroidal anti-inflammatory drugs, 1,3,4-thiadiazole, heterocyclic compounds, naproxenAbstract
Based on naproxen, in this study, a new series of 1,3,4-thiadiazol-2-thiol derivatives was prepared through the esterification of the carbonyl group (of naproxen) using thionyl chloride as an auxiliary agent with methanol, and then naproxen hydrazide was made, to be obtained using (CS2) and a basic media convert it to the potassium salt of dithiocarbazate. It was oxidized with concentrated sulfuric acid to a compound containing the thiol thiadiazole ring, and finally, through an alkylation reaction, the final compounds were produced (Gh1, Gh2, Gh3, Gh4). These compounds were characterized using infrared spectroscopy and proton nuclear magnetic resonance. Then, the anti-inflammatory effectiveness was evaluated in vivo by inducing acute inflammation in laboratory rats with egg whites.
The compounds were successfully synthesized with a percentage yield approaching 70%, and it was discovered that they are effective in reducing the thickness of the paw edema of the tested rats and have an anti-inflammatory influence similar to the effect of the reference substance (naproxen) some compounds were more effective than naproxen at some trial times, as or compound (Gh1) at time (T7) after (5) hours of practical experience.
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References
Bian M, Zhen D, Shen Q-K, Du H-H, Ma Q-Q, Quan Z-S. Structurally modified glycyrrhetinic acid derivatives as anti-inflammatory agents. Bioorganic Chemistry. 2021;107:104598.
Pannone E, Abbott R. What is known about the health effects of non-steroidal anti-inflammatory drug (NSAID) use in marathon and ultra-endurance running: a scoping review. BMJ Open Sport & Exercise Medicine. 2024;10(1):e001846.
Jahnavi K, Reddy PP, Vasudha B, Narender B. Non-steroidal anti-inflammatory drugs: an overview. Journal of Drug Delivery and Therapeutics. 2019;9(1-s):442-8.
Adams DH, Michael J, Bacon PA, Howie AJ, McConkey B, Adu D. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND RENAL FAILURE. The Lancet. 1986;327(8472):57-60.
Domper Arnal M-J, Hijos-Mallada G, Lanas A. Gastrointestinal and cardiovascular adverse events associated with NSAIDs. Expert Opinion on Drug Safety. 2022;21(3):373-84.
Sardar A, Abid O-u-R, Daud S, Shah BA, Shahid W, Ashraf M, et al. Identification of novel diclofenac acid and naproxen bearing hydrazones as 15-LOX inhibitors: Design, synthesis, in vitro evaluation, cytotoxicity, and in silico studies. Arabian Journal of Chemistry. 2022;15(12):104300.
Sokołowska P, Bleibel L, Owczarek J, Wiktorowska-Owczarek A. PPARγ, NF-κB and the UPR pathway as new molecular targets in the anti-inflammatory actions of NSAIDs: Novel applications in cancers and central nervous system diseases? Adv Clin Exp Med. 2024.
Hassan OM, Sarsam SW. Synthesis, characterization and preliminary anti-inflammatory evaluation of new etodolac derivatives. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512). 2019;28(1):106-12.
Naser AS. Design, synthesis and anti-inflammatory evaluation of new 2-amino heterocyclic derivatives of Naproxen: University of Baghdad; 2017.
Nasser NH, Hammud NH, Hasan SA, Abdalsadh AH, kareem Hussein A. Design and Synthesis of new Naproxen Analogues as Potential Anti-inflammatory Agents. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2017;17(1):9-.
Ryan PM, Scherry H, Pierson R, Wilson CD, Probe RA. NSAID use in orthopedic surgery: A review of current evidence and clinical practice guidelines. J Orthop Res. 2024;42(4):707-16.
Ammar YA, Salem MA, Fayed EA, Helal MH, El-Gaby MSA, Thabet HK. Naproxen derivatives: Synthesis, reactions, and biological applications. Synthetic Communications. 2017;47(15):1341-67.
Nedeljković N, Dobričić V, Bošković J, Vesović M, Bradić J, Anđić M, et al. Synthesis and investigation of anti-inflammatory activity of new thiourea derivatives of naproxen. Pharmaceuticals. 2023;16(5):666.
Moshawih S, Jarrar Q, Bahrin AA, Lim AF, Ming L, Goh HP. Evaluating NSAIDs in SARS-CoV-2: Immunomodulatory mechanisms and future therapeutic strategies. Heliyon. 2024;10(3):e25734.
Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochemical pharmacology. 2020;180:114147.
Cao Y, Khan A, Soltani A, Erfani-Moghadam V, Lup ANK, Aghaei M, et al. Spectroscopic, density functional theory, cytotoxicity and antioxidant activities of sulfasalazine and naproxen drugs combination. Arabian Journal of Chemistry. 2021;14(6):103190.
Dzionek A, Wojcieszyńska D, Marchlewicz A, Smułek W, Potocka I, Jałowiecki Ł, et al. Naproxen as environmental pollution, its effect on bacteria metabolism and degradation mechanism in immobilized Planococcus sp. S5. Chemical Engineering Journal. 2024;481:148174.
Ammar YA, Khalifa MM, Eisa SI, Ismail MMF. New Naproxen Analogs: Synthesis, Docking and Anti-Inflammatory Evaluation. Polycyclic Aromatic Compounds. 2022;42(6):3586-605.
Shah K, Mujwar S, Krishna G, Gupta JK. Computational design and biological depiction of novel naproxen derivative. ASSAY and Drug Development Technologies. 2020;18(7):308-17.
Shokri T, Sadeghi M, Hadidi S, Mohammadi S. Efficient fluorescence probe for detection of naproxen in pharmaceutical formulations and water samples using MPA-capped CdTe/ZnS core-shell nanocrystal-neutral red: Experimental and computational studies. Journal of Photochemistry and Photobiology A: Chemistry. 2024;452:115545.
Hussain MA, Shad I, Malik I, Amjad F, Tahir MN, Ullah N, et al. Design, characterization and enhanced bioavailability of hydroxypropylcellulose-naproxen conjugates. Arabian Journal of Chemistry. 2020;13(6):5717-23.
Siddiqui SZ, Rasool S, Shah SAA. Synthesis, spectral analysis and biological evaluation of sulfamoyl and 1, 3, 4-oxadiazole derivatives of 3-pipecoline. Pak J Pharm Sci. 2019;32(3):987-96.
Abdel-Tawab M, Zettl H, Schubert-Zsilavecz M. Nonsteroidal anti-inflammatory drugs: a critical review on current concepts applied to reduce gastrointestinal toxicity. Current medicinal chemistry. 2009;16(16):2042-63.
Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999;340(24):1888-99.
Cao Y, You Z, Cao Y, Li Y, Wong VKW, Chen M, et al. Synthesis and in vitro characterization of naproxen derivatives as novel anti-inflammatory agents. Journal of Molecular Structure. 2024;1309:138158.
Chawla G, Ranjan C, Kumar J, A Siddiqui A. Chemical modifications of ketoprofen (NSAID) in search of better lead compounds: A Review of literature from 2004-2016. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents). 2016;15(3):154-77.
Tziona P, Theodosis-Nobelos P, A Rekka E. Medicinal Chemistry approaches of controlling gastrointestinal side effects of non-steroidal anti-inflammatory drugs. Endogenous protective mechanisms and drug design. Medicinal Chemistry. 2017;13(5):408-20.
Pereira‐Leite C, Nunes C, Jamal SK, Cuccovia IM, Reis S. Nonsteroidal anti‐inflammatory therapy: a journey toward safety. Medicinal research reviews. 2017;37(4):802-59.
Hu Y, Li CY, Wang XM, Yang YH, Zhu HL. 1,3,4-Thiadiazole: synthesis, reactions, and applications in medicinal, agricultural, and materials chemistry. Chem Rev. 2014;114(10):5572-610.
Sahib HA, Dakhel ZA, Hadi MK. Synthesis and Preliminary Antimicrobial Activity Evaluation of New Amide Derivatives of 2-aminobenzothiazole. IJDDT. 2021;11(4):1259-61.
Abduljabbar TT, Hadi MK. Synthesis, characterization and antibacterial evaluation of some coumarin derivatives. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512). 2021;30(1):249-57.
Hassan T, Farhan MS. Synthesis of New Pyrimidine Derivatives From 3-Acetylcoumarin–Chalcone Hybrid and Evaluation Their Antimicrobial Activitغe their antimicrobial activity y. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512). 2024;33(1):33-45.
Pham EC, Truong TN, Dong NH, Vo DD, Hong Do TT. Synthesis of a series of novel 2-amino-5-substituted 1, 3, 4-oxadiazole and 1, 3, 4-thiadiazole derivatives as potential anticancer, antifungal and antibacterial agents. Medicinal Chemistry. 2022;18(5):558-73.
Janowska S, Paneth A, Wujec M. Cytotoxic Properties of 1,3,4-Thiadiazole Derivatives—A Review. Molecules. 2020;25(18):4309.
Anthwal T, Singh H, Nain S. 1, 3, 4-thiadiazole scaffold: Anti-microbial agents. Pharmaceutical Chemistry Journal. 2022;55(12):1345-58.
Patel HM, Noolvi MN, Sethi NS, Gadad AK, Cameotra SS. Synthesis and antitubercular evaluation of imidazo[2,1-b][1,3,4]thiadiazole derivatives. Arabian Journal of Chemistry. 2017;10:S996-S1002.
Janowska S, Khylyuk D, Bielawska A, Szymanowska A, Gornowicz A, Bielawski K, et al. New 1,3,4-Thiadiazole Derivatives with Anticancer Activity. Molecules. 2022;27(6):1814.
Abouzied AS, Al-Humaidi JY, Bazaid AS, Qanash H, Binsaleh NK, Alamri A, et al. Synthesis, molecular docking study, and cytotoxicity evaluation of some novel 1, 3, 4-thiadiazole as well as 1, 3-thiazole derivatives bearing a pyridine moiety. Molecules. 2022;27(19):6368.
Wassel MMS, Ammar YA, Elhag Ali GAM, Belal A, Mehany ABM, Ragab A. Development of adamantane scaffold containing 1,3,4-thiadiazole derivatives: Design, synthesis, anti-proliferative activity and molecular docking study targeting EGFR. Bioorganic Chemistry. 2021;110:104794.
Vogel ER, Jackson W, Masterson DS. Efficient esterification of oxidized l-glutathione and other small peptides. Molecules. 2015;20(6):10487-95.
Abdulhamza HM, Farhan MS. Synthesis, Characterization and Preliminary Anti-inflammatory Evaluation of New Fenoprofen Hydrazone Derivatives. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512). 2020;29(2):239-44.
Amir M, Shikha K. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2, 6-dichloroanilino) phenyl] acetic acid derivatives. European journal of medicinal chemistry. 2004;39(6):535-45.
El-Faham A, Al Marhoon Z, Abdel-Megeed A, Siddiqui M. An efficient and mild method for the synthesis and hydrazinolysis of N-glyoxylamino acid esters. Journal of chemistry. 2013;2013.
Kamms ZD, Hadi MK. Synthesis, Characterization and preliminary Anti-Microbial Evaluation of New Ibuprofen Hydrazide Derivatives. Pakistan Journal of Medical & Health Sciences. 2022;16(03):693-.
Hmood KS, Mahmood Kubba AAR, Al-bayati RI, Saleh AM. Synthesis, and Anti-Tumor Evaluation of Some New Flurbiprofen Derivatives against MCF-7 and WRL-68 Cell Lines. Indonesian Journal of Pharmacy/Majalah Farmasi Indonesia. 2021;32(1).
Wei M-X, Feng L, Li X-Q, Zhou X-Z, Shao Z-H. Synthesis of new chiral 2, 5-disubstituted 1, 3, 4-thiadiazoles possessing γ-butenolide moiety and preliminary evaluation of in vitro anticancer activity. European journal of medicinal chemistry. 2009;44(8):3340-4.
Hussein Sabzi NA, Jawad Al-Mudhafar MM. Synthesis, characterization, and antimicrobial evaluation of new Schiff bases derived from vanillic acid conjugated to heterocyclic 4H-1, 2, 4-triazole-3-thiol. Pharmacia (0428-0296). 2023;70(3).
Abbas AH. Synthesis, Docking Study and Cytotoxic Evaluation of New 2-Pyridine Derivatives: University of Baghdad; 2021.
Hu Y, Li C-Y, Wang X-M, Yang Y-H, Zhu H-L. 1, 3, 4-Thiadiazole: synthesis, reactions, and applications in medicinal, agricultural, and materials chemistry. Chemical reviews. 2014;114(10):5572-610.
Aliaa A-H, Farhan MS. Synthesis, Identification and Preliminary Pharmacological Evaluation of New Hydrazone and 1, 3, 4-oxadiazole Derivatives of Ketorolac. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512). 2024;33(1):113-22.
Siddiqui SZ, Rasool S, Shah SAA. Synthesis, spectral analysis and biological evaluation of sulfamoyl and 1, 3, 4-oxadiazole derivatives of 3-pipecoline. Pak J Pharm Sci. 2019;32(3):987-96.
Abbas AH, Elias AN, Fadhil AA. Synthesis, characterization and biological evaluation of new potentially active hydrazones of naproxen hydrazide. Der Pharma Chemica. 2015;7(10):93-101.
Barung EN, Dumanauw JM, Duri MF, Kalonio DE. Egg white-induced inflammation models: A study of edema profile and histological change of rat's paw. Journal of Advanced Pharmaceutical Technology & Research. 2021;12(2):109-12.
Mahdi MF, Raauf A, Kadhim F. Design, Synthesis and Acute Anti-Inflammatory Evaluation of New Non-Steroidal Anti-Inflammatory Agents Having 4-Thiazolidinone Pharmacophore. J Nat Sci Res. 2015;5(6):21-8.
Mousa TH, Elia A. Design, synthesis and preliminary pharmacological evaluation of new possible non-steroidal anti-inflammatory agents having the 5-(methylsulfonyl)-1, 2, 4-triazole-3-amine pharmacophore. Der Pharma Chemica. 2015;7(9):279-93.
APPAH J, AGATEMOR UM-M, IDAKWOJI PA, HASSAN SM, MOMOH T. Anti-inflammatory and Diuretic Activity of Aqueous Extract of Leptadenia hastata Leaves in Wistar Rats. Int J Curr Res Med Sci. 2021;7(5):10-6.
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