Applied Chemical Engineering

Design, synthesis, and in vitro biological activity of five- and six-membered heterocycles naproxen derivatives

Nagham Majid Abdulhassan

Chemistry Department, College of Science, Mustansiriyah University, Baghdad, 14022, Iraq

Abdul Jabar Kh. Atia

Chemistry Department, College of Science, Mustansiriyah University, Baghdad, 14022, Iraq

Falah S. Al-Fartusie

Chemistry Department, College of Science, Mustansiriyah University, Baghdad, 14022, Iraq

DOI: https://doi.org/10.59429/ace.v8i4.5740

Keywords: naproxen; triazole; biological activity; thiocarbohydrazide; heterocycles

---

Abstract

This research details the synthesis of new triazole derivatives from the anti-inflammatory drug naproxen and evaluates their biological activity. Naproxen was converted into a key intermediate by reacting it with thiocarbohydrazide. From comp. (1), a series of novel compounds, including (2), (3), and (4), were synthesized. The structures of these derivatives were confirmed through FT-IR, H1-NMR, and C13-NMR spectroscopy and melting point analysis.

The biological assessment revealed that the newly synthesized compounds possess potent anti-inflammatory effects. Compounds (1), (2), (3), and (4) were particularly active, showing 60.85% anti-inflammatory activity, which is significantly higher than naproxen's 53.3%. Furthermore, LD50 results indicated that the derivatives have low toxicity. These promising results warrant further research into their other potential pharmacological applications, such as antibacterial and antiviral properties.

---

References

[1]. Kadhem, S.A., Ali, S.M., Atia, A.J.K., Salih, R.H., Abdulrazaq, R.A. (2018), Synthesis, and study of biological activities of compounds derived from new imidazole derivative

[2]. Journal of Pharmaceutical Sciences and Research, 10(11), pp. 2818–2824.

[3]. Eliewi, A.G., Al-Garawi, Z.S., Al-Kazzaz, F.F., Atia, A.J.K (2021), Multi-target-directed imidazole derivatives for neurodegenerative diseases. Journal of Physics Conference Series, 1853(1), 012066

[4]. Hamid, A.A., Abdul-Rasheed, O.F., Mahdi, M.F., Atia, A.-J., (2022), Design, synthesis, characterization, and biological evaluation of new diazolebenzamide derivatives as glucokinase activators with antihyperglycemic activity Egyptian Journal of Chemistry, , 65(8), pp. 451–469

[5]. Hashim, Z.B., Atia, A.J.K., Al-Bayti, R.I., Al-Marjani, M.F., Salih, R.H. (2018), Synthesis of new 1,3-thiazole and 1,3-oxazole from 3-chlorobenzo[b]thiophene and evaluation of anti-bacterial activity, Journal of Pharmaceutical Sciences and Research, 2018, 10(6), pp. 1629–1634

[6]. Eliwi, A.G., Ali, Z.Z.M., Al-Saady, F.A., Abdulsada, S.H., Atia, A.J.K. (2020), Synthesis and acetylcholinesterase inhibitory activity of new oxazole and 1, 2, 4-triazole derivatives bearing carbamazepine as a nucleus. Aip Conference Proceedings, 2020, 2213, 020301

[7]. Frühauf, A., Behringer, M., & Meyer-Almes, F. J. (2023). Significance of five-membered heterocycles in human histone deacetylase inhibitors. Molecules, 28(15), 5686. ‏

[8]. Sivaganesan, P., Ganesan, L., VL, S., Pal, S., Dam, S., Sarkar, J., & Chaudhuri, S. (2025). Efficient, One‐Pot, Green Syntheses of Analogues of 3, 4‐Dihydro‐2H Pyrroles as Potential New Antifungal and Antibacterial Agents. ChemistrySelect, 10(3), e202404705. ‏

[9]. Obaid, R. J., Naeem, N., Mughal, E. U., Al-Rooqi, M. M., Sadiq, A., Jassas, R. S., ... & Ahmed, S. A. (2022). Inhibitory potential of nitrogen-, oxygen-, and sulfur-containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase. RSC advances, 12(31), 19764-19855. ‏

[10]. Nemr, M. T., AboulMagd, A. M., Hassan, H. M., Hamed, A. A., Hamed, M. I., & Elsaadi, M. T. (2021). Design, synthesis, and mechanistic study of new benzenesulfonamide derivatives as anticancer and antimicrobial agents via carbonic anhydrase IX inhibition. RSC advances, 11(42), 26241-26257

[11]. Ewieda, S. Y., Salem, M. M., Elshewy, A., Abdalla, M., El-Manawaty, M., Abdelhady, H. K., ... & Nemr, M. T. (2025). Discovery of novel thiazolopyrimidine derivatives targeting topoisomerase II: Design, synthesis, antiproliferative evaluation, molecular docking, and apoptosis-inducing activity. Bioorganic Chemistry, 108672. ‏

[12]. Mohamed, M. F., Salem, I. M., Fouad, A., Allam, R. M., Fadaly, W. A., Nemr, M. T., ... & Abou-Salim, M. A. (2025). Synthesis and apoptotic induction of sulfonamide-based chalcone hybrids as first-in-class dual histone deacetylase-carbonic anhydrase inhibitors with potential anti-tubulin activity. Bioorganic Chemistry, 108694. ‏

[13]. Abdul-Amir, R.M., Al-Fartusie, F.S., Atia, A.K (2023), Synthesis, anti-inflammatory, and study of histological changes in the mice liver of 1,3-oxazole and 3,3-dihydro pyrazole derivatives, Aip Conference Proceedings, 2834(1), 030015

[14]. Aboelez, M. O., Ali, M. A. E. A., Kamel, M. S., Fadaly, W. A., Nemr, M. T., &Ezelarab, H. A. (2025). Novel 3, 4-diaminothieno [2, 3-b] thiophene-2, 5-dicarbohydrazide-based scaffolds as EGFRWT, EGFRT790M, and tubulin polymerization inhibitors with anti-proliferative activity. Bioorganic Chemistry, 108728. ‏

[15]. Fadaly, W. A., Nemr, M. T., Abd El-Hameed, A. M., Mohamed, F. E., & Zidan, T. H. (2025). Design and synthesis of new pyrazole hybrids linked to oxime and nitrate moieties, such as COX-2 and EGFRL858R/T790M inhibitors and nitric oxide donors with dual anti-inflammatory/anti-proliferative activities. Bioorganic Chemistry, 108563. ‏

[16]. Sardar, A., Daud, S., Fakhar-e-Alam, M., Siddique, M. H., Ashraf, M., Shahid, W., ... & Afzal, M. (2022). Design, synthesis, in vitro, and in silico studies of naproxen derivatives as dual lipoxygenase and α-glucosidase inhibitors. Journal of Saudi Chemical Society, 26(3), 101468. ‏

[17]. Sardar, A., Daud, S., Shah, B. A., Shahid, W., Ashraf, M., Fatima, M., ... & Alissa, S. A. (2022). 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, 15(12), 104300. ‏

[18]. Sardar, A., Khan, S., Hussain, R., Daud, S., Rehman, W., Aziz, T., ... &Alasmari, A. F. (2024). Identification of in vitro α-glucosidase and urease inhibitory effect, and in silico studies of naproxen-derived 1,3,4-oxadiazole-based Schiff-base derivatives. Journal of Molecular Structure, 1305, 137712. ‏

[19]. Karati, D., Mahadik, K. R., & Kumar, D. (2022). Pyrazole scaffolds: centrality in anti-inflammatory and antiviral drug design. Medicinal Chemistry, 18(10), 1060-1072. ‏

[20]. Eliwi, A.G., Abdullah, A.M., Abdulsada, S.H., ... Rajab, I.M., Hussein, Z.A (2019), Synthesis and antibacterial activity of some new derivatives containing thiazole moiety and study of their effects on MAO enzyme activity (In vitro). Indian Journal of Public Health Research and Development, 10(1), pp. 1018–1025. ‏

[21]. Sarvaiya, B. H., Vaja, P. I., Paghdar, N. A., & Ghelani, S. M. (2024). Medicinal perspective of a promising scaffold—dihydropyrimidinones: A review. Journal of Heterocyclic Chemistry, 61(8), 1325-1348. ‏

[22]. Ali, K. A., Maity, A., Roy, S. D., Pramanik, S. D., Das, P. P., & Shaharyar, M. A. (2023). Insight into the mechanism of steroidal and non-steroidal anti-inflammatory drugs. In How synthetic drugs work (pp. 61-94). Academic Press. ‏

[23]. de Souza, M. M., Gini, A. L. R., Moura, J. A., Scarim, C. B., Chin, C. M., & Dos Santos, J. L. (2025). The prodrug approach as a strategy to enhance drug permeability. Pharmaceuticals, 18(3), 297. ‏

[24]. Narayanan, K. B. (2025). Enzyme-Based Anti-Inflammatory Therapeutics for Inflammatory Diseases. Pharmaceutics, 17(5), 606. ‏

[25]. Narayanan, K. B. (2025). Enzyme-Based Anti-Inflammatory Therapeutics for Inflammatory Diseases. Pharmaceutics, 17(5), 606. ‏

[26]. Teixeira, S., Castanheira, E. M., & Carvalho, M. A. (2025). Hydrazides as Powerful Tools in Medicinal Chemistry: Synthesis, Reactivity, and Biological Applications. Molecules, 30(13), 2852. ‏

[27]. Guan, Q., Xing, S., Wang, L., Zhu, J., Guo, C., Xu, C., ... & Sun, H. (2024). Triazoles in medicinal chemistry: physicochemical properties, bioisosterism, and application. Journal of Medicinal Chemistry, 67(10), 7788-7824. ‏

[28]. Ajmal, M., Mahato, A. K., Khan, M., Rawat, S., Husain, A., Almalki, E. B., ... & Rashid, M. (2024). Significance of Triazole in medicinal chemistry: advancement in drug design, reward, and biological activity. Chemistry & Biodiversity, 21(7), e202400637. ‏

[29]. Naeem, N., Mughal, E. U., Sadiq, A., Othman, G. A., & Shakoor, B. (2025). Recent Advances in 1, 2, 4‐Triazole‐Based Anticancer Agents: Structural Optimization, Mechanisms, and Therapeutic Potential (2022–2025). Archiv der Pharmazie, 358(7), e70059. ‏

[30]. Rohilla, S., Goyal, G., Berwal, P., & Mathur, N. (2024). A review on indole-triazole molecular hybrids as a leading edge in drug discovery: current landscape and future perspectives. Current topics in medicinal chemistry, 24(18), 1557-1588. ‏

[31]. Ahmadi, M., Bekeschus, S., Weltmann, K. D., von Woedtke, T., & Wende, K. (2022). Non-steroidal anti-inflammatory drugs: Recent advances in the use of synthetic COX-2 inhibitors. RSC medicinal chemistry, 13(5), 471-496. ‏

[32]. Ahmadi, M., Bekeschus, S., Weltmann, K. D., von Woedtke, T., & Wende, K. (2022). Non-steroidal anti-inflammatory drugs: Recent advances in the use of synthetic COX-2 inhibitors. RSC medicinal chemistry, 13(5), 471-496. ‏

[33]. Liu, Y., Yang, C., Zhang, J., Ihsan, A., Ares, I., Martínez, M., ... & Martínez, M. A. (2024). Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences of mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts. Expert Opinion on Drug Metabolism & Toxicology, 20(8), 765-785. ‏

[34]. Thiruchenthooran, V., Sánchez-López, E., &Gliszczyńska, A. (2023). Perspectives of the application of non-steroidal anti-inflammatory drugs in cancer therapy: Attempts to overcome their unfavorable side effects. Cancers, 15(2), 475. ‏

[35]. Sahoo, M. K., Agrawal, N., Lanjhiyana, S. K., Bharti, S. K., & Jaiswal, M. (2025). Therapeutic Perspective of Prodrugs of Non-Steroidal Anti-Inflammatory Drugs and Antioxidants: An Approach to Reduce Toxicity and Enhance Efficacy. Current Topics in Medicinal Chemistry. ‏

[36]. Nahra, d. m., mohite, p., &deshmukh, s. (2024). emerging pharmacological applications of N-heterocycles: pyrazole derivatives, imidazole derivatives, and triazole derivatives. Paving the Path to Discoveries and Unlocking the Secrets of N-Heterocycles, 148. ‏

[37]. Kapoor, K., Kaur, N., Sohal, H. S., Kaur, M., Singh, K., & Kumar, A. (2025). Drugs and Their Mode of Action: A Review on Sulfur-Containing Heterocyclic Compounds. Polycyclic Aromatic Compounds, 45(1), 136-175. ‏

[38]. Aly, A. A., Hassan, A. A., Mohamed, N. K., Abd El-Aal, A. S., Balboul, B. A., Nayl, A. A., ... & Ramadan, M. (2025). Synthesis, Reactions, and Biological Applications of 1, 2, 4-Triazoles: A Review. Current Organic Chemistry, 29(11), 841-868. ‏

[39]. Tajdari, M., Peyrovinasab, A., Bayanati, M., Rabbani, M. I. M., Abdolghaffari, A. H., &Zarghi, A. (2024). Dual COX-2/TNF-α Inhibitors as Promising Anti-inflammatory and Cancer Chemopreventive Agents: A Review. Iranian Journal of Pharmaceutical Research: IJPR, 23(1), e151312. ‏

[40]. Al-Wahaibi, L. H., Abdel-Rahman, M. H., El-Adl, K., Youssif, B. G., Brase, S., & Abdel-Aziz, S. A. (2024). New Diaryl-1, 2, 4-triazolo [3, 4-a] pyrimidine hybrids as selective COX-2/sEH dual inhibitors with potent analgesic/anti-inflammatory and cardioprotective properties. ACS omega, 9(31), 33494-33509. ‏

[41]. Douaa, M., & Sara, S. (2024). Screening of cytotoxic, antithrombotic, and thrombolytic activities of some products and by-products (Doctoral dissertation, university center of Abdelhafid Boussouf-Mila). ‏

[42]. Sharma, A., Baraiya, R., Prakash, S., Biswas, A., Chowdhury, B., & Sharma, A. (2025). Anti‐Inflammatory Potential of Fish‐Derived Bioactive Peptides: Molecular Mechanisms, Delivery Strategies, and Clinical Perspectives. Comprehensive Reviews in Food Science and Food Safety, 24(4), e70234. ‏

[43]. Rajkumar, M., Presley, S. D., Govindaraj, P., Kirubakaran, D., Farahim, Ali, T., ... & Latha, S. (2025). Synthesis of chitosan/PVA/copper oxide nanocomposite using Anacardium occidentale extract and evaluating its antioxidant, antibacterial, anti-inflammatory, and cytotoxic activities. Scientific Reports, 15(1), 3931. ‏

[44]. Iriawati, I., Vitasasti, S., Rahmadian, F. N. A., &Barlian, A. (2024). Isolation and characterization of plant-derived exosome-like nanoparticles from Carica papaya L. fruit and their potential as anti-inflammatory agents. PLoS One, 19(7), e0304335. ‏

[45]. Roman, B. H., Muzykiewicz-Szymańska, A., Florkowska, K., Tkacz, M., Wilk, B., Kucharski, Ł., ... & Nowak, A. (2025). The Use of Plants That Seal Blood Vessels in Preparations Applied Topically to the Skin: A Review. Molecules, 30(9), 1973. ‏

[46]. Kandel, A., Li, L., Wang, Y., Tuo, W., & Xiao, Z. (2024). Differentiation and Regulation of Bovine Th2 Cells In Vitro. Cells 2024, 13, 738. Kandel, A., Li, L., Wang, Y., Tuo, W., & Xiao, Z. (2024). Differentiation and Regulation of Bovine Th2 Cells In Vitro. Cells 2024, 13, 738. ‏

[47]. Islam, M. S., Al Ferdous, K., Amin, M. N., Kamruzzaman, M., & Islam, M. A. (2024). Impact of monosodium glutamate on the liver of chick embryo: histology, biochemical properties, and AVBD9 gene expression. Int. J. Agric. Biosci., 13, 76-84. ‏

[48]. Gurjar, S., Bhat, A. R., Upadhya, R., & Shenoy, R. P. (2025). Extracellular vesicle-mediated approaches for the diagnosis and therapy of MASLD: current advances and future prospects. Lipids in Health and Disease, 24(1), 5. ‏

[49]. Masserdotti, C. (2023). Canine and Feline Liver Cytology. John Wiley & Sons. ‏

[50]. Holte, C. F. (2024). Novel insights into the fenestrated scavenger endothelium of the liver sinusoid. ‏