dubi̇ted Duzce University Journal of Science and Technology 2148-2446 Duzce University 10.29130/dubited.1717358 Catalysis and Mechanisms of Reactions Kataliz ve Reaksiyon Mekanizmaları İzoksazol İçeren Antikanser İlaçlarındaki Gelişmeler: Sentezden Klinik Potansiyel Advances in Isoxazole-Containing Anticancer Drugs: From Synthesis to Clinical Potential https://orcid.org/0000-0002-1595-585X Berber Nurcan ÇANAKKALE ONSEKİZ MART UNİVERSİTY 04 19 2026 14 2 651 665 06 11 2025 03 18 2026 Copyright © 2013, Duzce University Journal of Science and Technology 2013 Duzce University Journal of Science and Technology

Kanser, dünya genelinde en yaygın ve ölümcül hastalıklar arasında yer almakta olup, tedaviye karşı gelişen dirençlerle başa çıkmak ve hastalık sonuçlarını iyileştirmek adına yeni terapötik stratejiler geliştirilmesi büyük önem taşımaktadır. Heterosiklik bileşikler, tıbbi kimya alanında uzun süredir temel yapı taşları olarak kabul edilmektedir. Özellikle izoksazol halkası, benzersiz elektronik yapısı ve hidrojen bağları etkileşimi potansiyeli nedeniyle kanser tedavisinde umut verici bir farmakofor olarak öne çıkmaktadır. Isoxazole, bir beş üyeli heterosiklik halka olup, 1 ve 2. pozisyonlarda azot ve oksijen atomları içerir. Bu yapısı sayesinde, izoksazol türevleri çeşitli enzimler ve reseptörlerle hızlı bir şekilde etkileşime girerek farklı biyolojik aktiviteler sergileyebilmektedir. Son yıllarda, izoksazol türevlerinin meme kanseri, akciğer kanseri, kolon kanseri ve lösemi gibi kanser türlerinde önemli antikanser etkinlikler gösterdiği rapor edilmiştir. Bu çalışmada, izoksazol türevlerinin çeşitli kanser türlerindeki biyolojik etkileri incelenmiştir. İzoksazol türevlerinin apoptozun indüksiyonu, anjiyogenezisin inhibisyonu, hücre döngüsünün duraklatılması ve tümör hücre proliferasyonunun baskılanması gibi anahtar kanser yollarını modüle etme potansiyeli vurgulanmıştır. Çalışmanın bulguları, izoksazol halkasının antikanser ajanlarının rasyonel tasarımı için değerli bir motif olduğunu ortaya koymaktadır. Ayrıca, izoksazol içeren bileşiklerin sentezi, biyolojik aktiviteleri ve potansiyel klinik uygulamaları üzerine yapılan literatür taraması, bu alandaki gelecekteki araştırmalar için önemli ipuçları sunmaktadır.

Cancer is one of the most common and deadly diseases worldwide, and the development of new therapeutic strategies to overcome treatment resistance and improve clinical outcomes remains a critical challenge. Heterocyclic compounds have long been recognized as fundamental building blocks in medicinal chemistry. Among them, the isoxazole ring has emerged as a promising pharmacophore in anticancer drug design due to its unique electronic properties and hydrogen-bonding capability. Isoxazole is a five-membered heterocyclic ring containing nitrogen and oxygen atoms at the 1st and 2nd positions, enabling diverse interactions with enzymes and receptors and resulting in a wide range of biological activities. In this review, scientific studies on the development of isoxazole-containing compounds as anticancer agents have been systematically examined from the past to the present. The selected studies were evaluated based on their reported anticancer activity, molecular mechanisms of action, and clinical development status. Isoxazole derivatives have demonstrated significant activity against various cancer types, including breast, lung, colorectal cancers, and leukemia, through mechanisms such as apoptosis induction, cell cycle arrest, kinase inhibition, and suppression of angiogenesis. Moreover, the clinical approval of certain isoxazole-based drugs further supports the translational potential of this scaffold. Overall, the isoxazole core represents a promising and clinically relevant pharmacophore for the development of next-generation targeted anticancer therapies.

 Heterocyclic coumponds Isoxazole derivatives Dipolar cycloaddition Anticancer agents Heterosiklik bileşikler izoksazol türevleri 1 3-dipolar sikloadisyon antikanser ajanları This research received no external funding. Agrawal, N., & Mishra, P. (2018). The synthetic and therapeutic expedition of isoxazole and its analogs. Medicinal Chemistry Research, 27(5), 1309-1344. https://doi.org/10.1007/s00044-018-2152-6 Algethami, F. K., Saidi, I., Abdelhamid, H. N., Elamin, M. R., Abdulkhair, B. Y., Chrouda, A., & Ben Jannet, H. (2021). Trifluoromethylated flavonoid-based isoxazoles as antidiabetic and anti-obesity agents: Synthesis, in vitro α-amylase inhibitory activity, molecular docking and structure–activity relationship analysis. Molecules, 26(17), Article 5214. https://doi.org/10.3390/molecules26175214 Alminderej, F., Ghannay, S., Elsamani, M. O., Alhawday, F., Albadri, A. E. A. E., Elbehairi, S. E. I., Alfaifi, M. Y., Kadri, A., & Aouadi, K. (2023). In vitro and in silico evaluation of antiproliferative activity of new isoxazolidine derivatives targeting EGFR: Design, synthesis, cell cycle analysis, and apoptotic inducers. Pharmaceuticals, 16(7), Article 1025. https://doi.org/10.3390/ph16071025 Altharawi, A., Enneiymy, M., Ait Elmachkouri, Y., & Aldakhil, T. (2025). Synthesis, characterization, DFT, and in-Silico analysis of isoxazole-thiazolidinone hybrids: Reactivity and anticancer potential assessed through pharmacological network, molecular dynamics, molecular docking, and ADMET analysis. Journal of Molecular Structure, 1336, Article 142088. https://doi.org/10.1016/j.molstruc.2025.142088 Anjum, R., & Raza, C. (2025). Carvone: A bioactive monoterpene with diverse pharmacological applications. Current Pharmacology Reports, 11(1), Article 22. https://doi.org/10.1007/s40495-025-00402-5 Ardestani, M., Khorsandi, Z., Keshavarzipour, F., Iravani, S., Sadeghi-Aliabadi, H., & Varma, R. S. (2022). Heterocyclic compounds as Hsp90 inhibitors: A perspective on anticancer applications. Pharmaceutics, 14(10), Article 2220. https://doi.org/10.3390/pharmaceutics14102220 Arya, J. S., Joseph, M. M., Sherin, D. R., Nair, J. B., Manojkumar, T. K., & Maiti, K. K. (2019). Exploring mitochondria-mediated intrinsic apoptosis by new phytochemical entities: An explicit observation of cytochrome c dynamics on lung and melanoma cancer cells. Journal of Medicinal Chemistry, 62(17), 8311-8329. https://doi.org/10.1021/acs.jmedchem.9b01098 Ashwini, N., Garg, M., Mohan, C. D., Fuchs, J. E., Rangappa, S., Anusha, S., Swaroop, T. R., Rakesh, K. S., Kanojia, D., Madan, V., Bender, A., Koeffler, H. P., Basappa, & Rangappa, K. S. (2015). Synthesis of 1, 2-benzisoxazole tethered 1, 2, 3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation. Bioorganic & Medicinal Chemistry, 23(18), 6157-6165. https://doi.org/10.1016/j.bmc.2015.07.069 Baaloudj, O., Scrano, L., Bufo, S. A., Modley, L. A. S., Lelario, F., Zizzamia, A. R., Emanuele, L., & Brienza, M. (2025). Environmental fate, ecotoxicity, and remediation of heterocyclic pharmaceuticals as emerging contaminants: A review of long-term risks and ımpacts. Organics, 6(1), Article 1. https://doi.org/10.3390/org6010001 Bąchor, U., Mączyński, M., & Sochacka-Ćwikła, A. (2025). Therapeutic potential of isoxazole–(Iso) oxazole hybrids: Three decades of research. International Journal of Molecular Sciences, 26(15), Article 7082. https://doi.org/10.3390/ijms26157082 Barbieri, R. L., & Ryan, K. J. (1981). Danazol: Endocrine pharmacology and therapeutic applications. American Journal of Obstetrics and Gynecology, 141(4), 453-463. https://doi.org/10.1016/0002-9378(81)90611-6 Bouzammit, R., Belchkar, S., El Fadili, M., Kanzouai, Y., Mujwar, S., Alanazi, M. M., Chalka, M., Nakkabi, A., Bakhouch, M.,Gal, E., Gaina, L. I., & Al Houari, G. (2024). New triazole-isoxazole hybrids as antibacterial agents: Design, synthesis, characterization, in vitro, and in silico studies. Molecules, 29(11), Article 2510. https://doi.org/10.3390/molecules29112510 Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), 229-263. https://doi.org/10.3322/caac.21834 Brough, P. A., Aherne, W., Barril, X., Borgognoni, J., Boxall, K., Cansfield, J. E., Cheung, K.-M. J., Collins, I., Davies, N. G. M., Drysdale, M. J., Dymock, B., Eccles, S. A., Finch, H., Fink, A., Hayes, A., Howes, R., Hubbard, R. E., James, K., Jordan, A. M., … Wright, L. (2008). 4,5-diarylisoxazole Hsp90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer. Journal of Medicinal Chemistry, 51(2), 196-218. https://doi.org/10.1021/jm701018h Burra, S., Voora, V., Rao, C. P., Kumar, P. V., Kancha, R. K., & Krupadanam, G. L. D. (2017). Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer activity against breast cancer cell lines. Bioorganic & Medicinal Chemistry Letters, 27(18), 4314-4318. https://doi.org/10.1016/j.bmcl.2017.08.033 Carruthers, W. (2013). Cycloaddition reactions in organic synthesis (Vol. 8). Elsevier. Chene, P., Garcia-Echeverria, C., Jensen, M. R., Quadt, C., Radimerski, T., & Schoepfer, J. (2016). Isoxazole compound for the treatment of cancer. U.S. Patent Application No. 15/096,397. Chikkula, K. V., & Raja, S. (2017). Isoxazole–a potent pharmacophore. International Journal of Pharmacy and Pharmaceutical Sciences, 9(7), 13-24. https://doi.org/10.22159/ijpps.2017.v9i7.19097 Dawood, K. M., Abdel-Gawad, H., Mohamed, H. A., & Badria, F. A. (2011). Synthesis, anti-HSV-1, and cytotoxic activities of some new pyrazole-and isoxazole-based heterocycles. Medicinal Chemistry Research, 20(7), 912-919. https://doi.org/10.1007/s00044-010-9420-4 Debela, D. T., Muzazu, S. G., Heraro, K. D., Ndalama, M. T., Mesele, B. W., Haile, D. C., Kitui, S. K., & Manyazewal, T. (2021). New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Medicine, 9(6), Article 20503121211034366. https://doi.org/10.1177/20503121211034366 Eliopoulos, G. M., & Huovinen, P. (2001). Resistance to trimethoprim-sulfamethoxazole. Clinical Infectious Diseases, 32(11), 1608-1614. https://doi.org/10.1086/320532 Emran, T. B., Shahriar, A., Mahmud, A. R., Rahman, T., Abir, M. H., Siddiquee, M. F. R., Ahmed, H., Rahman, N., Nainu, F., Wahyudin, E., Mitra, S., Dhama, K., Habiballah, M. M., Haque, S., İslam, A., & Hassan, M. M. (2022). Multidrug resistance in cancer: Understanding molecular mechanisms, immunoprevention and therapeutic approaches. Frontiers in Oncology, 12, Article 891652. https://doi.org/10.3389/fonc.2022.891652 Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015). Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer, 136(5), E359-E386. https://doi.org/10.1002/ijc.29210 Fox, R. I., Herrmann, M. L., Frangou, C. G., Wahl, G. M., Morris, R. E., Strand, V., & Kirschbaum, B. J. (1999). Mechanism of action for leflunomide in rheumatoid arthritis. Clinical Immunology, 93(3), 198-208. https://doi.org/10.1006/clim.1999.4777 Frazer, R., Arranz, J. Á., Estévez, S. V., Parikh, O., Krabbe, L. M., Vasudev, N. S., Dohaen, C., Marschner, N., Waddell, T., Ince, W., & Goebell, P. J. (2024). Tivozanib monotherapy in the frontline setting for patients with metastatic renal cell carcinoma and favorable prognosis. Current Oncology Reports, 26(12), 1639-1650. https://doi.org/10.1007/s11912-024-01613-7 Gaikwad, N. B., Bansod, S., Mara, A., Garise, R., Srinivas, N., Godugu, C., & Yaddanapudi, V. M. (2021). Design, synthesis, and biological evaluation of N-(4-substituted)-3-phenylisoxazolo [5,4–d]pyrimidin-4-amine derivatives as apoptosis-inducing cytotoxic agents. Bioorganic & Medicinal Chemistry Letters, 49, Article 128294. https://doi.org/10.1016/j.bmcl.2021.128294 Gunawardane, R. N., Nepomuceno, R. R., Rooks, A. M., Hunt, J. P., Ricono, J. M., Belli, B., & Armstrong, R. C. (2013). Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3-activated leukemia cells. Molecular Cancer Therapeutics, 12(4), 438-447. https://doi.org/10.1158/1535-7163.MCT-12-0305 Hawash, M., Jaradat, N., Abualhasan, M., Amer, J., Levent, S., Issa, S., Ibrahim, S., Ayaseh, A., Shtayeh, T., & Mousa, A. (2021). Synthesis, chemo-informatics, and anticancer evaluation of fluorophenyl-isoxazole derivatives. Open Chemistry, 19(1), 855-863. https://doi.org/10.1515/chem-2021-0078 Himo, F., Lovell, T., Hilgraf, R., Rostovtsev, V. V., Noodleman, L., Sharpless, K. B., & Fokin, V. V. (2005). Copper (I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. Journal of the American Chemical Society, 127(1), 210-216. https://doi.org/10.1021/ja0471525 Hu, F., & Szostak, M. (2015). Recent developments in the synthesis and reactivity of isoxazoles: Metal catalysis and beyond. Advanced Synthesis & Catalysis, 357(12), 2583-2614. https://doi.org/10.1002/adsc.201500319 Hu, J. K., Tang, X., Luo, G. L., Zhang, C., Wu, T. B., Wang, C., Shen, H., Zhao, X. F., Wu, X. S., Smaill, J. B., Xu, Y., Zhang, Y., & Xiang, Q. P. (2025). Discovery of 5-imidazole-3-methylbenz [d] isoxazole derivatives as potent and selective CBP/p300 bromodomain inhibitors for the treatment of acute myeloid leukemia. Acta Pharmacologica Sinica, 46(6), 1706-1721. https://doi.org/10.1038/s41401-025-01478-x Huisgen, R. (1963). 1,3‐dipolar cycloadditions: Past and future. Angewandte Chemie International Edition in English, 2(10), 565-598. https://doi.org/10.1002/anie.196305651 Hussain, K., Macrinici, V., Wathen, L., Balasubramanian, S. S., Minga, I., Gaznabi, S., Kwak, E., Wang, C. H., Iqbal, S. H., Pursnani, A., & Sarswat, N. (2022). Impact of tafamidis on survival in a real-world community-based cohort. Current Problems in Cardiology, 47(12), Article 101358. https://doi.org/10.1016/j.cpcardiol.2022.101358 Im, E.-J., Lee, C.-H., Moon, P.-G., Rangaswamy, G. G., Lee, B., Lee, J. M., Lee, J.-C., Jee, J.-G., Bae, J.-S., Kwon, T.-K., Kang, K.-W., Jeong, M.-S., Lee, J.-E., Jung, H.-S., Ro, H.-J., Jun, S., Kang, W., Seo, S.-Y., Cho, Y.-E., … & Baek, M.-C. (2019). Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A. Nature Communications, 10(1), Article 1387. https://doi.org/10.1038/s41467-019-09387-4 Jampilek, J. (2019). Heterocycles in medicinal chemistry. Molecules, 24(21), Article 3839. https://doi.org/10.3390/molecules24213839 Kakkar, S., & Narasimhan, B. (2019). A comprehensive review on biological activities of oxazole derivatives. BMC Chemistry, 13(1), Article 16. https://doi.org/10.1186/s13065-019-0531-9 Kamal, A., Bharathi, E. V., Reddy, J. S., Ramaiah, M. J., Dastagiri, D., Reddy, M. K., Visvanath, A., Reddy, T. L., Shaik, T. B., Pushpavilli, S. N. C. V. L., & Bhadra, M. P. (2011). Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents. European Journal of Medicinal Chemistry, 46(2), 691-703. https://doi.org/10.1016/j.ejmech.2010.12.004 Kaur, J., Singla, P., & Goel, N. (2015). Adsorption of oxazole and isoxazole on BNNT surface: A DFT study. Applied Surface Science, 328, 632-640. https://doi.org/10.1016/j.apsusc.2014.12.099 Kaur, K., Kumar, V., Sharma, A. K., & Gupta, G. K. (2014). Isoxazoline containing natural products as anticancer agents: A review. European Journal of Medicinal Chemistry, 77, 121-133. https://doi.org/10.1016/j.ejmech.2014.02.063 Keshavarzipour, F., Abbasi, M., Khorsandi, Z., Ardestani, M., & Sadeghi-Aliabadi, H. (2024). Design, synthesis and biological studies of new isoxazole compounds as potent Hsp90 inhibitors. Scientific Reports, 14(1), Article 28017. https://doi.org/10.1038/s41598-024-79051-5 Kidwai, M., Venktaramanan, R., Mohan, R., & Sapra, P. (2002). Cancer chemotherapy and heterocyclic compounds. Current Medicinal Chemistry, 9(12), 1209-1228. https://doi.org/10.2174/0929867023370059 Kim, J., Harper, A., McCormack, V., Sung, H., Houssami, N., Morgan, E., Mutebi, M., Garvey, G., Soerjomataram, I., & Fidler-Benaoudia, M. M. (2025). Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nature Medicine, 31(4), 1154–1162. https://doi.org/10.1038/s41591-025-03502-3 Kobayashi, S., & Jørgensen, K. A. (Eds.). (2002). Cycloaddition reactions in organic synthesis. John Wiley & Sons. Kong, A., Rea, D., Ahmed, S., Beck, J. T., López López, R., Biganzoli, L., Armstrong, A. C., Aglietta, M., Alba, E., Campone, M., Hsu Schmitz, S. F., Lefebvre, C., Akimov, M., & Lee, S. C. (2016). Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2positive breast cancer patients who have progressed on trastuzumabbased regimen. Oncotarget, 7(25), 37680-37692. https://doi.org/10.18632/oncotarget.8974 Koufaki, M., Fotopoulou, T., Kapetanou, M., Heropoulos, G. A., Gonos, E. S., & Chondrogianni, N. (2014). Microwave-assisted synthesis of 3,5-disubstituted isoxazoles and evaluation of their anti-ageing activity. European Journal of Medicinal Chemistry, 83, 508-515. https://doi.org/10.1016/j.ejmech.2014.06.046 Kumar, K. A., & Jayaroopa, P. (2013). Isoxazoles: Molecules with potential medicinal properties. International Journal of Pharmaceutical, Chemical And Biological Sciences, 3(2), 294-304. Kumbhare, R. M., Kosurkar, U. B., Ramaiah, M. J., Dadmal, T. L., Pushpavalli, S. N. C. V. L., & Pal-Bhadra, M. (2012). Synthesis and biological evaluation of novel triazoles and isoxazoles linked 2-phenyl benzothiazole as potential anticancer agents. Bioorganic & Medicinal Chemistry Letters, 22(17), 5424-5427. https://doi.org/10.1016/j.bmcl.2012.07.041 Leppik, I. E. (2004). Zonisamide: Chemistry, mechanism of action, and pharmacokinetics. Seizure, 13, S5-S9. https://doi.org/10.1016/j.seizure.2004.04.016 Lingala, A. K., Mothe, T., Murahari, K. K., Desireddi, J. R., Maiti, B., & Manchal, R. (2022). Design, synthesis and anticancer evaluation of isoxazole fused thiazole-oxazole derivatives. Chemical Data Collections, 41, Article 100907. https://doi.org/10.1016/j.cdc.2022.100907 Maiuolo, L., De Nino, A., Algieri, V., & Nardi, M. (2017). Microwave-assisted 1,3-dipolar cyclo-addition: Recent advances in synthesis of isoxazolidines. Mini-Reviews in Organic Chemistry, 14(2), 136-142. https://doi.org/10.2174/1570193X14666170206123513 Majirská, M., Pilátová, M. B., Kudličková, Z., Vojtek, M., & Diniz, C. (2024). Targeting hematological malignancies with isoxazole derivatives. Drug Discovery Today, 29(8), Article 104059. https://doi.org/10.1016/j.drudis.2024.104059 Malik, U., & Pal, D. (2024). Cancer-fighting ısoxazole compounds: Sourcing nature's potential and synthetic advancements- a comprehensive review. ES Food and Agroforestry, 15, Article 1052. https://dx.doi.org/10.30919/esfaf1052 Martis, G. J., & Gaonkar, S. L. (2025). Advances in isoxazole chemistry and their role in drug discovery. RSC Advances, 15(11), 8213-8243. https://doi.org/10.1039/D4RA08339C Montenegro, R. C., Clark, P. G. K., Howarth, A., Wan, X., Ceroni, A., Siejka, P., Nunez-Alanso, G. A., Monteiro, O., Rogers, C., Gamble, V., Burbano, R., Brennan, P. E., Tallant, C., Ebner, D., Fedorov, O., O’Neill, E., Knapp, S., Dixon, D., & Müller, S. (2016). BET inhibition as a new strategy for the treatment of gastric cancer. Oncotarget, 7(28), 43997-44012. https://doi.org/10.18632/oncotarget.9766 Möller, H. J. (2005). Risperidone: A review. Expert Opinion on Pharmacotherapy, 6(5), 803-818. https://doi.org/10.1517/14656566.6.5.803 Ni, T., Chi, X., Xie, F., Li, L., Wu, H., Hao, Y., Wang, X., Zhang, D., & Jiang, Y. (2023). Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents. European Journal of Medicinal Chemistry, 246, Article 115007. https://doi.org/10.1016/j.ejmech.2022.115007 Olsson, R., Wiholm, B.-E., Sand, C., Zettergren, L., Hultcrantz, R., & Myrhed, M. (1992). Liver damage from flucloxacillin, cloxacillin and dicloxacillin. Journal of Hepatology, 15(1-2), 154-161. https://doi.org/10.1016/0168-8278(92)90029-O Ormrod, D., Wellington, K., & Wagstaff, A. J. (2002). Valdecoxib. Drugs, 62, 2059-2071. https://doi.org/10.2165/00003495-200262140-00005 Padwa, A. (1976). Intramolecular 1,3‐dipolar cycloaddition reactions. Angewandte Chemie International Edition in English, 15(3), 123-136. https://doi.org/10.1002/anie.197601231 Pandey, S., Nagpal, R., Thakur, A., Bari, S. S., Nanda, P. K., & Thapar, R. (2024). Synthesis of novel isoxazole/dihydroisoxazole tethered β-lactam hybrids via regiospecific 1,3-dipolar cycloaddition methodology on 3-phenylthio-β-lactams. Journal of Sulfur Chemistry, 45(6), 950-971. https://doi.org/10.1080/17415993.2024.2398574 Pandhurnekar, C. P., Pandhurnekar, H. C., Mungole, A. J., Butoliya, S. S., & Yadao, B. G. (2023). A review of recent synthetic strategies and biological activities of isoxazole. Journal of Heterocyclic Chemistry, 60(4), 537-565. https://doi.org/10.1002/jhet.4586 Pineiro, M., & Pinho e Melo, T. M. V. D. (2009). Microwave‐assisted 1,3‐dipolar cycloaddition: An eco‐friendly approach to five‐membered heterocycles. European Journal of Organic Chemistry, 2009(31), 5287-5307. https://doi.org/10.1002/ejoc.200900644 Plumet, J. (2020). 1,3‐dipolar cycloaddition reactions of nitrile oxides under “non‐conventional” conditions: Green solvents, ırradiation, and continuous flow. ChemPlusChem, 85(10), 2252-2271. https://doi.org/10.1002/cplu.202000448 Poster, D. S., Bruno, S., Penta, J., Neil, G. L., & McGovren, J. P. (1981). Acivicin: An antitumor antibiotic. Cancer Clinical Trials, 4(3), 327-330. Reddy, S. T., Mendonza, J. J., Makani, V. K. K., Bhadra, M. P., & Uppuluri, V. M. (2020). Synthesis of some novel methyl β-orsellinate based 3, 5-disubstituted isoxazoles and their anti-proliferative activity: Identification of potent leads active against MCF-7 breast cancer cell. Bioorganic Chemistry, 105, Article 104374. https://doi.org/10.1016/j.bioorg.2020.104374 Rodrigues, F. C., Kumar, N. V. A., Hari, G., Pai, K. S. R., & Thakur, G. (2021). The inhibitory potency of isoxazole-curcumin analogue for the management of breast cancer: A comparative in vitro and molecular modeling investigation. Chemical Papers, 75(1), 5995-6008. https://doi.org/10.1007/s11696-021-01775-9 Rusu, A., Moga, I. M., Uncu, L., & Hancu, G. (2023). The role of five-membered heterocycles in the molecular structure of antibacterial drugs used in therapy. Pharmaceutics, 15(11), Article 2554. https://doi.org/10.3390/pharmaceutics15112554 Sakly, R., Edziri, H., Askri, M., Knorr, M., Louven, K., Strohmann, C., & Mastouri, M. (2017). Synthesis of new spirooxindole‐fused isoxazoline/triazole and isoxazoline/isoxazole derivatives from three‐component 1,3‐dipolar cycloaddition. Journal of Heterocyclic Chemistry, 54(6), 3554-3564. https://doi.org/10.1002/jhet.2981 Schwartz, M. A. (1962). Monoamine oxidase inhibition by isocarboxazid. The Journal of Pharmacology and Experimental Therapeutics, 135(1), 1-6. https://doi.org/10.1016/S0022-3565(25)26184-5 Singh, M. S., Chowdhury, S., & Koley, S. (2016). Progress in 1,3-dipolar cycloadditions in the recent decade: An update to strategic development towards the arsenal of organic synthesis. Tetrahedron, 72(13), 1603-1644. https://doi.org/10.1016/j.tet.2016.02.031 Smith, L. I. (1938). Aliphatic diazo compounds, nitrones, and structurally analogous compounds. Systems capable of undergoing 1,3-additions. Chemical Reviews, 23(2), 193-285. https://doi.org/10.1021/cr60075a001 Sochacka-Ćwikła, A., Mączyński, M., & Regiec, A. (2022). FDA-approved small molecule compounds as drugs for solid cancers from early 2011 to the end of 2021. Molecules, 27(7), Article 2259. https://doi.org/10.3390/molecules27072259 Sutherland, R., Croydon, E. A. P., & Rolinson, G. N. (1970). Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin. British Medical Journal, 4, 455-460. https://doi.org/10.1136/bmj.4.5733.455 Sysak, A., & Obmińska-Mrukowicz, B. (2017). Isoxazole ring as a useful scaffold in a search for new therapeutic agents. European Journal of Medicinal Chemistry, 137, 292-309. https://doi.org/10.1016/j.ejmech.2017.06.002 Taldone, T., Gozman, A., Maharaj, R., & Chiosis, G. (2008). Targeting Hsp90: small-molecule inhibitors and their clinical development. Current Opinion in Pharmacology, 8(4), 370-374. https://doi.org/10.1016/j.coph.2008.06.015 Thakur, A., Verma, M., Setia, P., Bharti, R., Sharma, R., Sharma, A., Negi, N. P., Anand, V., & Bansal, R. (2023). DFT analysis and in vitro studies of isoxazole derivatives as potent antioxidant and antibacterial agents synthesized via one-pot methodology. Research on Chemical Intermediates, 49(3), 859-883. https://doi.org/10.1007/s11164-022-04910-7 Vashisht, K., Sethi, P., Bansal, A., & Bansal, P. (2025). Antimicrobial activity of isoxazole derivatives: A brief overview. Vietnam Journal of Chemistry. 63(2), 195-213. https://doi.org/10.1002/vjch.202400029 Veeraswamy, B., Kurumurthy, C., Kumar, G. S., Rao, P. S., Thelakkat, K., Kotamraju, S., & Narsaiah, B. (2012). Synthesis of novel 5-substituted isoxazole-3-carboxamide derivatives and cytotoxicity studies on lung cancer cell line. Indian Journal of Chemistry Section B: Organic Chemistry Including Medicinal Chemistry, 51(9), 1369–1375. Verma, H., Snehi, V., Pathak, D., Saha, S., & Kumar, S. (2022). Comprehensive Witting approach toward advancements in synthetic strategies and the pharmacological evaluation of isoxazole analogues through the angle of medicinal chemistry. International Journal of Scientific Development and Research, 7(12), 1191–1205. Vieira, A. A., Bryk, F. R., Conte, G., Bortoluzzi, A. J., & Gallardo, H. (2009). 1, 3-Dipolar cycloaddition reaction applied to synthesis of new unsymmetric liquid crystal compounds-based isoxazole. Tetrahedron Letters, 50(8), 905-908. https://doi.org/10.1016/j.tetlet.2008.12.021 Wagner, E., Wietrzyk, J., Psurski, M., Becan, L., & Turlej, E. (2020). Synthesis and anticancer evaluation of novel derivatives of isoxazolo [4,5-e][1,2,4]triazepine derivatives and potential inhibitors of protein kinase C. ACS Omega, 6(1), 119-134. https://doi.org/10.1021/acsomega.0c03801 Wang, X., Hu, Q., Tang, H., & Pan, X. (2023). Isoxazole/Isoxazoline skeleton in the structural modification of natural products: A review. Pharmaceuticals, 16(2), Article 228. https://doi.org/10.3390/ph16020228 Watterson, S. H., Guo, J., Spergel, S. H., Langevine, C. M., Moquin, R. V., Shen, D. R., Yarde, M., Cvijic, M. E., Banas, D., Liu, R., Suchard, S. J., Gillooly, K., Taylor, T., Rex-Rabe, S., Shuster, D. J., McIntyre, K. W., Cornelius, G., D’Arienzo, C., Marino, A., … Dyckman, A. J. (2016). Potent and selective agonists of sphingosine 1-phosphate 1 (S1P1): Discovery and SAR of a novel isoxazole based series. Journal of Medicinal Chemistry, 59(6), 2820-2840. https://doi.org/10.1021/acs.jmedchem.6b00089 Wazalwar, S. S., Banpurkar, A. R., & Perdih, F. (2023). Synthesis, crystal structure and molecular docking study of novel isoxazole derivatives as CYP450 inhibitors in search of anticancer agents. Journal of Biomolecular Structure and Dynamics, 41(19), 9476-9491. https://doi.org/10.1080/07391102.2022.2142667 Yang, Z., Li, P., & Gan, X. (2018). Novel pyrazole-hydrazone derivatives containing an isoxazole moiety: Design, synthesis, and antiviral activity. Molecules, 23(7), Article 1798. https://doi.org/10.3390/molecules23071798 Zheng, R., Feng, F., Zhang, Z., Fu, J., Su, Q., Zhang, Y., & Gu, Q. (2020). Microwave-assisted efficient synthesis of 3-substituted bis-isoxazole ether bearing 2-chloro-3-pyridyl via 1,3-dipolar cycloaddition. Molecular Diversity, 24(2), 423-435. https://doi.org/10.1007/s11030-019-09973-0 Zhu, J., Mo, J., Lin, H. Z., Chen, Y., & Sun, H. P. (2018). The recent progress of isoxazole in medicinal chemistry. Bioorganic & Medicinal Chemistry, 26(12), 3065-3075. https://doi.org/10.1016/j.bmc.2018.05.013 Zimecki, M., Bąchor, U., & Mączyński, M. (2018). Isoxazole derivatives as regulators of immune functions. Molecules, 23(10), Article 2724. https://doi.org/10.3390/molecules23102724