Generic placeholder image

Letters in Drug Design & Discovery

Author(s): Mohammed Hawash*, Nidal Jaradat, Murad Abualhasan, Mohammad Qneibi, Hama Rifai, Tala Saqfelhait, Yaqeen Shqirat, Alaa Nazal, Salam Omarya, Tymaa Ibrahim, Shorooq Sobuh, Abdulraziq Zarour and Ahmed Mousa

DOI: 10.2174/1570180819666220819151002

DownloadDownload PDF Flyer Cite As
Evaluation of Cytotoxic, COX Inhibitory, and Antimicrobial Activities of Novel Isoxazole-carboxamide Derivatives

Page: [1994 - 2002] Pages: 9

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Isoxazole derivatives are one of the heterocyclic structures that have various biological activities.

Objective: This study aimed to design and synthesize novel isoxazole derivatives and evaluate their cytotoxic, cyclooxygenase (COX) inhibitory, and antimicrobial activities.

Methods: Coupling reactions of aniline derivatives and isoxazole carboxylic acid have been established to synthesize chloro-fluorophenyl-isoxazole carboxamide derivatives. The synthesized compounds were characterized using 1H, 13C-NMR, IR, and HRMS spectrum analysis and evaluated by MTS, COX kit, and antimicrobial microdilution assays.

Results: The synthesized compounds showed moderate to potent cytotoxic activity against all the screened cancer cell lines (except 2b against HepG2) with an IC50 range of 0.107-77.83 μg/ml. The results showed that the most potent compound against cervical cancer cell line (HeLa) was the 2b compound, with an IC50 value of 0.11±0.10 μg/ml, which is less than the IC50 for the potent anticancer drug Doxorubicin. While the 2a and 2b compounds have potential antiproliferative activities against Hep3B with IC50 doses of 2.774±0.53 and 3.621±1.56 μg/ml, respectively. Furthermore, 2c compound was the most active against MCF7, with an IC50 value of 1.59±1.60 μg/ml. In addition, the most potent isoxazole derivative against the COX1 enzyme was the 2b compound, with an IC50 value of 0.391 μg/ml, and compound 2a had a good selectivity ratio of 1.44 compared to the Ketoprofen positive control. However, compound 2c showed antifungal activity against Candida albicans with an MIC value of 2.0 mg/ml in comparison to the antifungal drug Fluconazole (MIC = 1.65 mg/ml).

Conclusion: The synthesized compounds could be candidates for anticancer drugs in the future, and other analogues and cytotoxicity evaluations should be conducted

Keywords: Isoxazole, anticancer, doxorubicin, COX, ketoprofen, antifungal.

Graphical Abstract

[1]
Feng, R.M.; Zong, Y.N.; Cao, S.M.; Xu, R.H. Current cancer situation in China: Good or bad news from the 2018 Global Cancer Statistics? Cancer Commun. (Lond.), 2019, 39(1), 22.
[http://dx.doi.org/10.1186/s40880-019-0368-6] [PMID: 31030667]
[2]
Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends-an update. Cancer Epidemiol. Biomarkers Prev., 2016, 25(1), 16-27.
[http://dx.doi.org/10.1158/1055-9965.EPI-15-0578] [PMID: 26667886]
[3]
Wenzel, E.S.; Singh, A.T.K. Cell-cycle checkpoints and aneuploidy on the path to cancer. In Vivo, 2018, 32(1), 1-5.
[PMID: 29275292]
[4]
Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med., 2019, 380(15), 1450-1462.
[http://dx.doi.org/10.1056/NEJMra1713263] [PMID: 30970190]
[5]
Hartke, J.; Johnson, M.; Ghabril, M. The diagnosis and treatment of hepatocellular carcinoma. Semin. Diagn. Pathol., 2017, 34(2), 153-159.
[http://dx.doi.org/10.1053/j.semdp.2016.12.011] [PMID: 28108047]
[6]
Li, H.; Wu, X.; Cheng, X. Advances in diagnosis and treatment of metastatic cervical cancer. J. Gynecol. Oncol., 2016, 27(4), e43.
[http://dx.doi.org/10.3802/jgo.2016.27.e43] [PMID: 27171673]
[7]
Fisusi, F.A.; Akala, E.O. Drug combinations in breast cancer therapy. Pharm. Nanotechnol., 2019, 7(1), 3-23.
[http://dx.doi.org/10.2174/2211738507666190122111224] [PMID: 30666921]
[8]
Akram, M.; Iqbal, M.; Daniyal, M.; Khan, A.U. Awareness and current knowledge of breast cancer. Biol. Res., 2017, 50(1), 33.
[http://dx.doi.org/10.1186/s40659-017-0140-9] [PMID: 28969709]
[9]
Wang, J.J.; Lei, K.F.; Han, F. Tumor microenvironment: Recent advances in various cancer treatments. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(12), 3855-3864.
[PMID: 29949179]
[10]
Ratan, R.; Patel, S.R. Chemotherapy for soft tissue sarcoma. Cancer, 2016, 122(19), 2952-2960.
[http://dx.doi.org/10.1002/cncr.30191] [PMID: 27434055]
[11]
Dzierzbicka, K.; Kołodziejczyk, A. Combretastatin A-4 and its analogues as antineoplastic agents. ChemInform, 2004, 78(3), 323-341.
[http://dx.doi.org/10.1002/chin.200428234]
[12]
West, C.M.; Price, P. Combretastatin A4 phosphate. Anticancer Drugs, 2004, 15(3), 179-187.
[http://dx.doi.org/10.1097/00001813-200403000-00001] [PMID: 15014350]
[13]
Nainwal, L.M.; Alam, M.M.; Shaquiquzzaman, M.; Marella, A.; Kamal, A. Combretastatin-based compounds with therapeutic characteristics: A patent review. Expert Opin. Ther. Pat., 2019, 29(9), 703-731.
[http://dx.doi.org/10.1080/13543776.2019.1651841] [PMID: 31369715]
[14]
Kamal, A.; Reddy, V.S.; Shaik, A.B.; Kumar, G.B.; Vishnuvardhan, M.V.; Polepalli, S.; Jain, N. Synthesis of (Z)-(arylamino)-pyrazolyl/isoxazolyl-2-propenones as tubulin targeting anticancer agents and apoptotic inducers. Org. Biomol. Chem., 2015, 13(11), 3416-3431.
[http://dx.doi.org/10.1039/C4OB02449D] [PMID: 25661328]
[15]
Hawash, M.; Jaradat, N.; Abualhasan, M.; Amer, J.; Levent, S.; Issa, S.; Ibrahim, S.; Ayaseh, A.; Shtayeh, T.; Mousa, A. Synthesis, chemo-informatics, and anticancer evaluation of fluorophenyl-isoxazole derivatives. Open Chem., 2021, 19(1), 855-863.
[http://dx.doi.org/10.1515/chem-2021-0078]
[16]
Jadala, C.; Sathish, M.; Anchi, P.; Tokala, R.; Lakshmi, U.J.; Reddy, V.G.; Shankaraiah, N.; Godugu, C.; Kamal, A. Synthesis of combretastatin-A4 carboxamidest that mimic sulfonyl piperazines by a molecular hybridization approach: In vitro cytotoxicity evaluation and inhibition of tubulin polymerization. ChemMedChem, 2019, 14(24), 2052-2060.
[http://dx.doi.org/10.1002/cmdc.201900541] [PMID: 31674147]
[17]
Hawash, M.; Eid, A.M.; Jaradat, N.; Abualhasan, M.; Amer, J.; Naser Zaid, A.; Draghmeh, S.; Daraghmeh, D.; Daraghmeh, H.; Shtayeh, T.; Sawaftah, H.; Mousa, A. Synthesis and biological evaluation of benzodioxole derivatives as potential anticancer and antioxidant agents. Heterocycl. Commun., 2020, 26(1), 157-167.
[http://dx.doi.org/10.1515/hc-2020-0105]
[18]
Caneschi, W.; Enes, K.B.; Carvalho de Mendonça, C.; de Souza Fernandes, F.; Miguel, F.B.; da Silva Martins, J.; Le Hyaric, M.; Pinho, R.R.; Duarte, L.M.; Leal de Oliveira, M.A.; Dos Santos, H.F.; Paz Lopes, M.T.; Dittz, D.; Silva, H.; Costa Couri, M.R. Synthesis and anticancer evaluation of new lipophilic 1,2,4 and 1,3,4-oxadiazoles. Eur. J. Med. Chem., 2019, 165, 18-30.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.001] [PMID: 30654237]
[19]
Eid, A.M.; Hawash, M.; Amer, J.; Jarrar, A.; Qadri, S.; Alnimer, I.; Sharaf, A.; Zalmoot, R.; Hammoudie, O.; Hameedi, S.; Mousa, A. Synthesis and biological evaluation of novel isoxazole-amide analogues as anticancer and antioxidant agents. BioMed Res. Int., 2021, 2021, 6633297.
[http://dx.doi.org/10.1155/2021/6633297] [PMID: 33763478]
[20]
Hawash, M.; Jaradat, N.; Bawwab, N.; Salem, K.; Arafat, H.; Hajyousef, Y.; Shtayeh, T.; Sobuh, S. Design, synthesis, and biological evaluation of phenyl-isoxazole-carboxamide derivatives as anticancer agents. Heterocycl. Commun., 2021, 27(1), 133-141.
[http://dx.doi.org/10.1515/hc-2020-0134]
[21]
Inceler, N.; Yılmaz, A.; Baytas, S.N. Synthesis of ester and amide derivatives of 1-phenyl-3-(thiophen-3-yl)-1 H-pyrazole-4-carboxylic acid and study of their anticancer activity. Med. Chem. Res., 2013, 22(7), 3109-3118.
[http://dx.doi.org/10.1007/s00044-012-0317-2]
[22]
Inceler, N.; Ozkan, Y.; Turan, N.N.; Kahraman, D.C.; Cetin-Atalay, R.; Baytas, S.N. Design, synthesis and biological evaluation of novel 1,3-diarylpyrazoles as cyclooxygenase inhibitors, antiplatelet and anticancer agents. MedChemComm, 2018, 9(5), 795-811.
[http://dx.doi.org/10.1039/C8MD00022K] [PMID: 30108969]
[23]
Agrawal, N.; Mishra, P. The synthetic and therapeutic expedition of isoxazole and its analogs. Med. Chem. Res., 2018, 27(5), 1309-1344.
[http://dx.doi.org/10.1007/s00044-018-2152-6] [PMID: 32214770]
[24]
Barmade, M.A.; Murumkar, P.R.; Sharma, M.K.; Yadav, M.R. Medicinal chemistry perspective of fused isoxazole derivatives. Curr. Top. Med. Chem., 2016, 16(26), 2863-2883.
[http://dx.doi.org/10.2174/1568026616666160506145700] [PMID: 27150366]
[25]
Yong, J.P.; Lu, C.Z.; Wu, X. Potential anticancer agents. I. Synthesis of isoxazole moiety containing quinazoline derivatives and preliminarily in vitro anticancer activity. Anticancer. Agents Med. Chem., 2015, 15(1), 131-136.
[http://dx.doi.org/10.2174/1871520614666140812105445] [PMID: 25142319]
[26]
Naresh Kumar, R.; Jitender Dev, G.; Ravikumar, N.; Krishna Swaroop, D.; Debanjan, B.; Bharath, G.; Narsaiah, B.; Nishant Jain, S.; Gangagni Rao, A. Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl)pyrido[2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents. Bioorg. Med. Chem. Lett., 2016, 26(12), 2927-2930.
[http://dx.doi.org/10.1016/j.bmcl.2016.04.038] [PMID: 27130357]
[27]
Hawash, M.; Kahraman, D.C.; Ergun, S.G.; Cetin-Atalay, R.; Baytas, S.N. Synthesis of novel indole-isoxazole hybrids and evaluation of their cytotoxic activities on hepatocellular carcinoma cell lines. BMC Chem., 2021, 15(1), 66.
[http://dx.doi.org/10.1186/s13065-021-00793-8] [PMID: 34930409]
[28]
Sysak, A.; Obmińska-Mrukowicz, B. Isoxazole ring as a useful scaffold in a search for new therapeutic agents. Eur. J. Med. Chem., 2017, 137, 292-309.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.002] [PMID: 28605676]
[29]
Govindappa, V.K.; Prabhashankar, J.; Khatoon, B.B.A.; Ningappa, M.B.; Kariyappa, A.K. Synthesis of 3, 5-diaryl-isoxazole-4-carbonitriles and their efficacy as antimicrobial agents. Pharma Chem., 2012, 4(6), 2283-2287.
[30]
Pedada, S.R.; Yarla, N.S.; Tambade, P.J.; Dhananjaya, B.L.; Bishayee, A.; Arunasree, K.M.; Philip, G.H.; Dharmapuri, G.; Aliev, G.; Putta, S.; Rangaiah, G. Synthesis of new secretory phospholipase A2-inhibitory indole containing isoxazole derivatives as anti-inflammatory and anticancer agents. Eur. J. Med. Chem., 2016, 112, 289-297.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.025] [PMID: 26907155]
[31]
Kumar, C.; Veeresh, B.; Ramesha, K.; Raj, C.; Mahadevaiah, K.; Prasad, S.; Naveen, S.; Madaiah, M.; Rangappa, K. Antidiabetic studies of 1-benzhydryl-piperazine sulfonamide and carboxamide derivatives. J Applicable Chem, 2017, 6(2), 232-240.
[32]
Majewsky, M.; Wagner, D.; Delay, M.; Bräse, S.; Yargeau, V.; Horn, H. Antibacterial activity of sulfamethoxazole transformation products (TPs): General relevance for sulfonamide TPs modified at the para position. Chem. Res. Toxicol., 2014, 27(10), 1821-1828.
[http://dx.doi.org/10.1021/tx500267x] [PMID: 25211553]
[33]
Mani, S.S.R.; Iyyadurai, R. Cloxacillin induced agranulocytosis: A rare adverse event of a commonly used antibiotic. Int. J. Immunopathol. Pharmacol., 2017, 30(3), 297-301.
[http://dx.doi.org/10.1177/0394632017724320] [PMID: 28786715]
[34]
Conti, P.; Roda, G.; Stabile, H.; Vanoni, M.A.; Curti, B.; De Amici, M. Synthesis and biological evaluation of new amino acids structurally related to the antitumor agent acivicin. Farmaco, 2003, 58(9), 683-690.
[http://dx.doi.org/10.1016/S0014-827X(03)00107-1] [PMID: 13679161]
[35]
Cheng, L.; Wang, H.; Wang, Z.; Huang, H.; Zhuo, D.; Lin, J. Leflunomide inhibits proliferation and induces apoptosis via suppressing autophagy and PI3K/Akt signaling pathway in human bladder cancer cells. Drug Des. Devel. Ther., 2020, 14, 1897-1908.
[http://dx.doi.org/10.2147/DDDT.S252626] [PMID: 32546957]
[36]
Assali, M.; Abualhasan, M.; Sawaftah, H.; Hawash, M.; Mousa, A. Synthesis, biological activity, and molecular modeling studies of pyrazole and triazole derivatives as selective COX-2 inhibitors. J. Chem., 2020, 2020, 6393428.
[37]
Khalil, A.; Jaradat, N.; Hawash, M.; Issa, L. In vitro biological evaluation of benzodioxol derivatives as antimicrobial and antioxidant agents. Arab. J. Sci. Eng., 2021, 46(6), 5447-5453.
[http://dx.doi.org/10.1007/s13369-021-05332-0]
[38]
Nacak, S.; ÖKÇELİK, B.; ÜNLÜ, S.; ŞAHİN, S.; ÖZKAN, S.; ABBASOĞLU, S. Synthesis and antimicrobial activity of some new mannich bases of 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives. Turkish J. Pharm. Sci, 2005, 2(1), 25-33.
[39]
Hawash, M.; Jaradat, N.; Hameedi, S.; Mousa, A. Design, synthesis and biological evaluation of novel benzodioxole derivatives as COX inhibitors and cytotoxic agents. BMC Chem., 2020, 14(1), 54.
[http://dx.doi.org/10.1186/s13065-020-00706-1] [PMID: 32944715]
[40]
Jaradat, N.; Khasati, A.; Hawi, M.; Qadi, M.; Amer, J.; Hawash, M. In vitro antitumor, antibacterial, and antifungal activities of phenylthio-ethyl benzoate derivatives. Arab. J. Sci. Eng., 2021, 46(6), 5339-5344.
[http://dx.doi.org/10.1007/s13369-020-05114-0]
[41]
Jaradat, N.; Hawash, M.; Murad, N.A. Synthesis and biological evaluation of benzodioxol derivatives as cyclooxygenase Inhibitors. Lett. Drug Des. Discov., 2020, 17(1), 1117-1125.
[http://dx.doi.org/10.2174/1570180817999200420114402]