In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition

Belgin Sever; Mehlika Dilek Altıntop; Gülşen Akalın Çiftçi

In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition

Abstract

Lung cancer is not only the most commonly diagnosed cancer type but also the leading cause of cancer related deaths throughout the world. The advanced methods for lung cancer therapy have focused on the development of new targeted agents. Cyclooxygenase (COX) is one of the most crucial targets for lung cancer therapy. In the current work, new compounds (1-12) containing 1,3,4-oxadiazole and pyrimidine cores within the acetamide framework were synthesized and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast (healthy) cell lines using MTT assay. Compounds 2 and 10 were defined as the most cytotoxic agents in this series (IC50 <3.9 µg/mL) compared to cisplatin (IC50= 26.00±3.00 µg/mL) without revealing cytotoxicity to healthy cells. The COX-1 and COX-2 inhibitory profiles of compounds 2 and 10 were also searched for providing a mechanistic insight into their potent antiproliferative effects. Compound 2 inhibited COX-1 and COX-2 dually and significantly (59.52% and 50.59%, respectively), whereas compound 10 exhibited no significant COX-1 and COX-2 inhibition. Molecular docking studies indicated that compound 2 showed its COX-1 and COX-2 inhibitory potencies with favourable interactions in the active sites of COX-1 and COX-2. Both in vitro and in silico assays accentuated that potential, orally bioavailable drug-like compound 2 attracted notice for the COX-targeted anti-lung cancer treatment.

Keywords

References

[1] Lemjabbar-Alaoui H, Hassan OU, Yang YW, Buchanan P. Lung cancer: Biology and treatment options. Biochim Biophys Acta. 2015; 1856: 189-210. [CrossRef]
[2] Herbst RS, Morgensztern D, Boshoff C. The biology and management of nonsmall cell lung cancer. Nature. 2018; 553: 446-454. [CrossRef]
[3] Zappa C, Mousa SA. Non-small cell lung cancer: Current treatment and future advances. Transl Lung Cancer Res. 2016; 469(3): 743-747. [CrossRef]
[4] Murphey LJ, Williams MK, Sanchez SC, Byrne LM, Csiki I, Oates JA, Johnson DH, Morrowa JD. Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: Determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and those with lung cancer. Anal Biochem. 2004; 332: 266-275. [CrossRef]
[5] Wood SL, Pernemalm M, Crosbie, PA, Whetton AD. Molecular histology of lung cancer: From targets to treatments. Cancer Treat Rev. 2015; 41(4): 361-375. [CrossRef]
[6] Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran Jr. WJ, Wu, YL, Paz-Ares L. Lung cancer: Current therapies and new targeted treatments. Lancet. 2017; 389: 299-311. [CrossRef]
[7] Ruiz-Ceja KA, Chirino, YI. Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection. Biomed Pharmacother. 2017; 90: 24-37. [CrossRef]
[8] Clària, J. Cyclooxygenase-2 biology. Curr Pharm Des. 2003; 9(27): 2177-2190. [CrossRef]

[9] Blanke C. Role of COX-2 inhibitors in cancer therapy. Cancer Invest. 2004; 22(2): 271-282. [CrossRef]
[10] Mann JR, Backlund MG, DuBois RN. Mechanisms of disease: Inflammatory mediators and cancer prevention. Nat Clin Pract Oncol. 2005; 2(4): 202-210. [CrossRef]
[11] Jeon YT, Song YS. Cyclooxygenases in cancer: chemoprevention and sensitization to conventional therapies. Mini Rev Med Chem. 2006; 6(7): 827-833. [CrossRef]
[12] Goradel NH, Najafi M, Salehi E, Farhood B, Mortezaee K. Cyclooxygenase-2 in cancer: A review. J Cell Physiol. 2019; 234(5): 5683-5699. [CrossRef]
[13] Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, Ogawa M, Mitsudomi T, Sugiura T, Takahashi T. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res. 1998; 58(17): 3761-3764.
[14] Khuri FR, Wu H, Lee JJ, Kemp BL, Lotan R, Lippman SM, Feng L, Hong WK, Xu XC. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res. 2001; 7(4): 861- 867.
[15] Altorki NK, Port JL, Zhang F, Golijanin D, Thaler HT, Duffield-Lillico AJ, Subbaramaiah K, Dannenberg, AJ. Chemotherapy induces the expression of cyclooxygenase-2 in non-small cell lung cancer. Clin Cancer Res. 2005; 11(11): 4191-4197. [CrossRef]
[16] Yuan A, Yu CJ, Shun CT, Luh K-T, Kuo S-H, Lee Y-C, Yang P-C. Total cyclooxygenase-2 mRNA levels correlate with vascular endothelial growth factor mRNA levels, tumor angiogenesis and prognosis in non-small cell lung cancer patients. Int J Cancer. 2005; 115(4): 545-555. [CrossRef]
[17] Lim ES, Rhee YH, Park MK, Shim B-S, Ahn K-S, Kang H, Yoo H-S, Kim S-H. DMNQ S-64 induces apoptosis via caspase activation and cyclooxygenase-2 inhibition in human nonsmall lung cancer cells. Ann N Y Acad Sci. 2007; 1095: 7-18. [CrossRef]
[18] Greene ER, Huang S, Serhan CN, Panigrahy D. Regulation of inflammation in cancer by eicosanoids. Prostaglandins Other Lipid Mediat. 2011; 96(1-4): 27-36. [CrossRef],
[19] Mattsson JS, Bergman B, Grinberg M, Edlund K, Marincevic M, Jirström K, Pontén F, Hengstler JG, Rahnenführer J, Karlsson MG, Karlsson C, Helenius G, Botling J, Micke P, Gulyas M. Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression. Cancer Lett. 2015; 356(2 Pt B): 837-845. [CrossRef]
[20] Dai P, Li J, Ma XP, Huang J, Meng JJ, Gong P. Efficacy and safety of COX-2 inhibitors for advanced non-small-cell lung cancer with chemotherapy: A meta-analysis. Onco Targets Ther. 2018; 11: 721-730. [CrossRef]
[21] Zhang P, He D, Song E, Jiang M, Song Y. Celecoxib enhances the sensitivity of non-small-cell lung cancer cells to radiation-induced apoptosis through downregulation of the Akt/mTOR signaling pathway and COX-2 expression [published correction appears in PLoS One. 2019; 14(10):e0224843]. PLoS One. 2019; 14(10): e0223760. [CrossRef]
[22] Yu T, Lao X, Zheng H. Influencing COX-2 activity by COX related pathways in inflammation and cancer. Mini Rev Med Chem. 2016; 16(15): 1230-1243. [CrossRef]
[23] Pannunzio A, Coluccia M. Cyclooxygenase-1 (COX-1) and COX-1 inhibitors in cancer: A review of oncology and medicinal chemistry literature. Pharmaceuticals (Basel). 2018; 11(4): 101. [CrossRef]
[24] Vitale P, Scilimati A, Perrone MG. Update on SAR studies toward new COX-1 selective inhibitors. Curr Med Chem. 2015; 22(37): 4271-4292. [CrossRef]
[25] Rocca B, Morosetti R, Habib A, Maggiano N, Zassadowski F, Ciabattoni G, Chomienne C, Papp B, Ranelletti FO. Cyclooxygenase-1, but not -2, is upregulated in NB4 leukemic cells and human primary promyelocytic blasts during differentiation. Leukemia. 2004; 18(8): 1373-1379. [CrossRef]
[26] Saha R, Tanwar O, Marella A, Alam MM, Akhter M. Recent updates on biological activities of oxadiazoles. Mini Rev Med Chem. 2013; 13(7): 1027-1046. [CrossRef]
[27] Bajaj S, Asati V, Singh J, Roy PP. 1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents. Eur J Med Chem. 2015; 97: 124-141. [CrossRef]
[28] Miller K, Moul JW, Gleave M, Fizazi K, Nelson JB, Morris T, Nathan FE, McIntosh S, Pemberton K, Higano CS. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2013; 16(2): 187-192. [CrossRef]
[29] Fargualy AM, Habib NS, Ismail KA, Hassan AM, Sarg MT. Synthesis, biological evaluation and molecular docking studies of some pyrimidine derivatives. Eur J Med Chem. 2013; 66: 276-295. [CrossRef]
[30] Kaur R, Kaur P, Sharma S, Singh G., Mehndiratta S, Bedi PMS, Nepali K. Anti-cancer pyrimidines in diverse scaffolds: a review of patent literature. Recent Pat Anticancer Drug Discov. 2015; 10(1): 23-71. [CrossRef]
[31] Myungho J, Joo Bin K, Hyeonho J, Younho L, Hua L, Sein K, Hyun JS, Juhee K, Hwan K, Hyunkyung K, Kyung-Ah S, Jung Beom S, Nam Doo K, Jiyoon S, Sun-Hwa L. Prepn. of 2,4,5-substituted pyrimidine derivs. for preventing or treating cancer. PCT Int. Appl. (2019), WO 2019177375 A1 20190919.
[32] Yildirim M, Yildirim A, Mutlu, E. Novel thiazolo[3,2-c] pyrimidine based anticancer compounds. PCT Int. Appl. (2019), WO 2019240681 A2 20191219.
[33] Bedi S, Khan SA, AbuKhader MM, Alam P, Siddiqui NA, Husain A. A comprehensive review on Brigatinib - A wonder drug for targeted cancer therapy in non-small cell lung cancer. Saudi Pharm J. 2018; 26(6): 755-763. [CrossRef]
[34] Zhang Y, Lv H, Luo L, Xu Y, Pan Y, Wang Y, Lin H, Xiong J, Guo P, Zhang J, Li X, Ye F. Design, synthesis and pharmacological evaluation of N4,N6-disubstituted pyrimidine-4,6-diamine derivatives as potent EGFR inhibitors in non-small cell lung cancer. Eur J Med Chem. 2018; 157: 1300-1325. [CrossRef]
[35] De la Torre BG, Albericio F. The pharmaceutical industry in 2017. An analysis of FDA drug approvals from the perspective of molecules. Molecules. 2018; 23: 533. [CrossRef]
[36] Dannhardt G, Kiefer W. Cyclooxygenase inhibitors--current status and future prospects. Eur J Med Chem. 2001; 36(2): 109-126. [CrossRef]
[37] Orjales A, Mosquera R, López B, Olivera R, Labeaga L, Núñez MT. Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors. Bioorg Med Chem. 2008; 16(5): 2183-2199. [CrossRef]
[38] Sondhi SM, Singhal N, Johar M, Reddy BS, Lown JW. Heterocyclic compounds as inflammation inhibitors. Curr Med Chem. 2002; 9(10): 1045-1074. [CrossRef]
[39] Güngör EM, Altıntop MD, Sever B, Akalın Çiftçi G. Design, synthesis, in vitro and in silico evaluation of new hydrazone-based antitumor agents as potent Akt inhibitors. Lett Drug Des Discov. 2020. [CrossRef]
[40] Altıntop MD, Sever B, Akalın Çiftçi G, Turan-Zitouni G, Kaplancıklı ZA, Özdemir A. Design, synthesis, in vitro and in silico evaluation of a new series of oxadiazole-based anticancer agents as potential Akt and FAK inhibitors. Eur J Med Chem. 2018; 155: 905-924. [CrossRef]
[41] Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63. [CrossRef]
[42] Rimon G., Sidhu RS, Lauver DA, Lee JY, Sharma NP, Yuan C, Frieler RA, Trievel RC, Lucchesi BR, Smith WL. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc Natl Acad Sci USA. 2010; 107: 28-33 [CrossRef] , [43] Dong L, Yuan C, Orlando BJ, Malkowski MG, Smith WL. Fatty acid binding to the allosteric subunit of cyclooxygenase-2 relieves a tonic inhibition of the catalytic subunit. J Biol Chem. 2016; 291: 25641-25655. [CrossRef]

Details

Primary Language

English

Subjects

Pharmaceutical Chemistry

Journal Section

Research Article

Authors

Belgin Sever ^*
Türkiye

Mehlika Dilek Altıntop
Türkiye

Gülşen Akalın Çiftçi
Türkiye

Publication Date

June 27, 2025

Submission Date

July 1, 2020

Acceptance Date

August 27, 2020

Published in Issue

Year 2020 Volume: 24 Number: 5

IZ

https://izlik.org/JA85DK45DT

Cite

RIS / Bibtex

APA

Sever, B., Altıntop, M. D., & Akalın Çiftçi, G. (2025). In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition. Journal of Research in Pharmacy, 24(5), 656-669. https://izlik.org/JA85DK45DT

AMA

1.Sever B, Altıntop MD, Akalın Çiftçi G. In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition. J. Res. Pharm. 2025;24(5):656-669. https://izlik.org/JA85DK45DT

Chicago

Sever, Belgin, Mehlika Dilek Altıntop, and Gülşen Akalın Çiftçi. 2025. “In Vitro and in Silico Assessment of Antiproliferative Activity of New Acetamides Bearing 1,3,4-Oxadiazole and Pyrimidine Cores via COX Inhibition”. Journal of Research in Pharmacy 24 (5): 656-69. https://izlik.org/JA85DK45DT.

EndNote

Sever B, Altıntop MD, Akalın Çiftçi G (June 1, 2025) In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition. Journal of Research in Pharmacy 24 5 656–669.

IEEE

[1]B. Sever, M. D. Altıntop, and G. Akalın Çiftçi, “In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition”, J. Res. Pharm., vol. 24, no. 5, pp. 656–669, June 2025, [Online]. Available: https://izlik.org/JA85DK45DT

ISNAD

Sever, Belgin - Altıntop, Mehlika Dilek - Akalın Çiftçi, Gülşen. “In Vitro and in Silico Assessment of Antiproliferative Activity of New Acetamides Bearing 1,3,4-Oxadiazole and Pyrimidine Cores via COX Inhibition”. Journal of Research in Pharmacy 24/5 (June 1, 2025): 656-669. https://izlik.org/JA85DK45DT.

JAMA

1.Sever B, Altıntop MD, Akalın Çiftçi G. In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition. J. Res. Pharm. 2025;24:656–669.

MLA

Sever, Belgin, et al. “In Vitro and in Silico Assessment of Antiproliferative Activity of New Acetamides Bearing 1,3,4-Oxadiazole and Pyrimidine Cores via COX Inhibition”. Journal of Research in Pharmacy, vol. 24, no. 5, June 2025, pp. 656-69, https://izlik.org/JA85DK45DT.

Vancouver

1.Belgin Sever, Mehlika Dilek Altıntop, Gülşen Akalın Çiftçi. In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition. J. Res. Pharm. [Internet]. 2025 Jun. 1;24(5):656-69. Available from: https://izlik.org/JA85DK45DT