Facile synthesis and anticancer activity of novel dihydropyrimidinone derivatives

Bhat, Mashooq A.; Al-Omar, Mohamed A.; Naglah, Ahmed M.; Al-Dhfyan, Abdullah

doi:10.2478/pjct-2022-0004

Abstract

The enaminone, (2E)-3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one was prepared by refluxing 3,4,5-trimethoxy acetophenone with dimethylformamide dimethylacetal (DMF–DMA) without solvent for 12 h. The dihydropyrimidinone derivatives (1–9) were prepared by reacting enaminone, substituted benzaldehydes and urea in glacial acetic acid. The compounds (1–9) were synthesized in significant yield using one step multicomponent reaction. Structures of all the novel synthesized compounds were characterized and confirmed by various spectroscopic methods. The compounds were evaluated for their anti-cancer activity against HepG2 cancer cell line. Compound 9 displayed significant anti-cancer activity. During the apoptotic assay, it showed a significant increase in necrosis from 1.97% to 12.18% as compared to the control. Mechanism of anti-proliferation was performed by cell cycle distribution assay, which showed a decrease in G2+M from 12.90 to 8.13 as compared to control.

References

1. Folkers, K., Harwood, H.J. & Johnson, T.B. (1932). Researches on pyrimidines. cxxx. synthesis of 2-keto-1,2,3,4-tetrahydropyrimidines. J. Am. Chem. Soc. 54, 3751. DOI: 10.1021/ja01348a040.10.1021/ja01348a040
Search in Google Scholar Back to article
2. Atwal, K.S., Ahmed, S.Z., Bird, J.E., Delaney, C.L., Dickinson, K.E., Ferrara, F.N., Hedberg, A., Miller, A.V., Moreland, S. & O’Reilly, B.C. (1992). Dihydropyrimidine angiotensin II receptor antagonists. J. Med. Chem. 35, 4751−4763. DOI: 10.1021/jm00103a014.10.1021/jm00103a014
Search in Google Scholar Back to article
3. Rana, K., Kaur, B. & Kumar, B. (2004). Synthesis and antihypertensive activity of some dihydropyrimidines. Indian J. Chem. 43, 1553−1557.10.1002/chin.200445173
Search in Google Scholar Back to article
4. Rovnyak, G.C., Kimball, S.D., Beyer, B., Cucinotta, G., DiMarco, J.D., Gougoutas, J., Hedberg, A., Malley, M., Mc-Carthy, J.P., Zhang, R. & Moreland, S. (1995). Calcium entry blockers and activators: conformational and structural determinants of dihydropyrimidine calcium channel modulators. J. Med. Chem. 38, 119–29. DOI: 10.1021/jm00001a017.10.1021/jm00001a017
Search in Google Scholar Back to article
5. Atwal, K.S., Swanson, B.N., Unger, S.E., Floyd, D.M., Moreland, S., Hedberg, A. & Reilly, B.C.O. (1991). Dihydropyrimidine calcium channel blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. J. Med. Chem. 34, 806−811. DOI: 10.1021/jm00106a048.10.1021/jm00106a048
Search in Google Scholar Back to article
6. Kappe, C.O. (1993). 100 years of the Biginelli dihydropyrimidine synthesis. Tetrahedron, 49, 6937−6963. DOI: 10.1016/S0040-4020(01)87971-0.10.1016/S0040-4020(01)87971-0
Search in Google Scholar Back to article
7. Beena, K.P., Suresh, R., Rajasekaran, A. & Manna, P.K. (2016). Dihydropyrimidinones- a versatile Scaffold with diverse biological activity. J. Pharm. Sci. & Res. 8, 741−746.
Search in Google Scholar Back to article
8. Jalali, M., Mahdavi, M., Memarian, H.R., Ranjbar, M., Soleymani, M., Fassihi, A. & Abedi, D. (2012). Antimicrobial evaluation of some novel derivatives of 3,4-dihydropyrimidine-2(1H)-One. Res. Pharm. Sci. 7, 243–247. PMID: 23248675.
Search in Google Scholar Back to article
9. Pramanik, T., Pathan, A.H., Gupta, R., Singh, J. & Singh, S. (2015). Dihydropyrimidinone derivatives: green synthesis and effect of electronic factor on their antimicrobial properties. Res. J. Pharm. Biol. Chem. Sci. 6, 1152–1157.
Search in Google Scholar Back to article
10. Shaikh, A. & Meshram, J.S. (2015). Design, synthesis and pharmacological assay of novel azo derivatives of dihydropyrimidinones. Cogent Chem. 1, 1019809. DOI:10.1080/23 312009.2015.1019809.10.1080/23312009.2015.1019809
Search in Google Scholar Back to article
11. Liu, Y., Liu, J., Zhang, R., Guo, Y., Wang, H., Meng, Q., Sun, Y. & Liu, Z. (2019). Synthesis, characterization, and anticancer activities evaluation of compounds derived from 3,4-dihydropyrimidin-2(1H)-One. Molecules, 24, 891. DOI: 10.3390/molecules24050891.10.3390/molecules24050891642957930832453
Search in Google Scholar Back to article
12. Abdel-Latif, N.A., Sabry, N.M., Mohamed, A.M. & Abdulla, M.M. (2007). Synthesis, analgesic, and antiparkinsonian profiles of some pyridine, pyrazoline, and thiopyrimidine derivatives. Monatshefte fur Chemie., 138, 715–724. DOI: 10.1007/s00706-007-0656-8.10.1007/s00706-007-0656-8
Search in Google Scholar Back to article
13. Bairagi, K.M., Younis, N.S., Emeka, P.M., Sangtani, E., Gonnade, R.G., Venugopala, K.N., Alwassil, O.I., Khalil, H.E. & Nayak, S.K. (2020). Antidiabetic activity of dihydropyrimidine scaffolds and structural insight by single crystal x-ray studies. Med. Chem. 16, 996–1003. DOI: 10.2174/15734064166661912 27123048.10.2174/1573406416666191227123048
Search in Google Scholar Back to article
14. Farghaly, A.M., AboulWafa, O.M., Elshaier, Y.A.M., Badawi, W.A., Haridy, H.H. & Mubarak, H.A.E. (2019). Design, synthesis, and antihypertensive activity of new pyrimidine derivatives endowing new pharmacophores. Med. Chem. Res. 28, 360–379. DOI: 10.1007/s00044-019-02289-6.10.1007/s00044-019-02289-6
Search in Google Scholar Back to article
15. Silva, G.C.O., Correa, J.R., Rodrigues, M.O., Alvim, H.G.O., Guido, B.C., Gatto, C.C., Wanderley, K.A., Fioramonte, M., Gozzo, F.C., De Souza, R.O.M.A. & Neto, B.A.D. (2015). The Biginelli reaction under batch and continuous flow conditions: catalysis, mechanism and antitumoral activity. RSC Adv. 5, 48506–48515. DOI: 10.1039/c5ra07677c.10.1039/C5RA07677C
Search in Google Scholar Back to article
16. Soumyanarayanan, U., Bhat, V.G., Kar, S.S. & Mathew J.A. (2012). Monastrol mimic Biginelli dihydropyrimidinone derivatives: synthesis, cytotoxicity screening against HepG2 and HeLa cell lines and molecular modeling study. Org. Med. Chem. Lett., 2, 23. DOI: 10.1186/2191-2858-2-23.10.1186/2191-2858-2-23351814322691177
Search in Google Scholar Back to article
17. Romagnoli, R., Baraldi, P.G., Cara, C.L., Hamel, E., Basso, G., Bortolozzi, R. & Viola, G. (2010). Synthesis and biological evaluation of 2-(3’,4’,5’-trimethoxybenzoyl)-3-aryl/arylaminobenzo[b]thiophene derivatives as a novel class of antiproliferative agents. Eur. J. Med. Chem. 45, 5781–5791. DOI: 10.1016/j.ejmech.2010.09.038.10.1016/j.ejmech.2010.09.038307496620933308
Search in Google Scholar Back to article
18. Tseng, H.H., Chuah, Q.Y., Yang, P.M., Chen, C.T., Chao, J.C., Lin, M.D. & Chiu, S.J. (2012). Securin enhances the anti-cancer effects of 6-methoxy-3-(3’,4’,5’-trimethoxy-benzoyl)-1H-indole (BPR0L075) in human colorectal cancer cells. PLoS One, 7, e36006. DOI: 10.1371/journal.pone.0036006.10.1371/journal.pone.0036006333855722563433
Search in Google Scholar Back to article
19. Bhat, M.A., Al-Omar, M.A., Ghabbour, H. & Naglah, A. (2018). A one-pot Biginelli synthesis and sharacterization of novel dihydropyrimidinone derivatives containing piperazine/morpholine moiety. Molecules, 23, 1559. DOI: 10.3390/molecules23071559.10.3390/molecules23071559609959629954138
Search in Google Scholar Back to article
20. Bhat, M. A., Al-Omar, M. A., Naglah., A. & Al-Dhfyan, A. (2020). Biginelli synthesis of novel dihydropyrimidinone derivatives containing phthalimide moiety. J. Chem. 2020, 1−10. DOI: 10.1155/2020/4284628.10.1155/2020/4284628
Search in Google Scholar Back to article
21. Bhat, M.A., Al-Omar, M.A., Naglah, A. & Khan, A.A. (2019). Enaminone-derived pyrazoles with antimicrobial activity. J. Chem. 2019, 1−10. DOI: 10.1155/2019/2467970.10.1155/2019/2467970
Search in Google Scholar Back to article
22. Bhat, M.A., Al-Omar, M.A., Khan, A.A., Alanazi, A.M. & Naglah, A.M. (2019). Synthesis and antihepatotoxic activity of dihydropyrimidinone derivatives linked with 1, 4-benzodioxane. Drug Des. Devel. Ther. 13, 2393. DOI 10.2147/DDDT.S198865.10.2147/DDDT.S198865664700831409973
Search in Google Scholar Back to article
23. Bhat, M.A., Al-Omar, M.A. & Naglah, A. (2018). Synthesis and in vivo anti-ulcer evaluation of some novel piperidine linked dihydropyrimidinone derivatives. J. Enzyme. Inhib. Med. Chem. 33, 978−988. DOI: 10.1080/14756366.2018.1474212.10.1080/14756366.2018.1474212600990829792357
Search in Google Scholar Back to article
24. Bhat, M.A., Ahmed, A.F., Wen, Z.H., Al-Omar, M.A. & Abdel-Aziz, H.A. (2017). Synthesis, anti-inflammatory and neuroprotective activity of pyrazole and pyrazolo[3,4-d] pyridazine bearing 3,4,5-trimethoxyphenyl. Med. Chem. Res. 26, 1557−1566. DOI: 10.1007/s00044-017-1870-5.10.1007/s00044-017-1870-5
Search in Google Scholar Back to article
25. Bhat, M.A., Al-Omar, M.A., Naglah, A., Kalmouch, A. & Al-Dhfyan, A. (2019). Synthesis and characterization of novel Biginelli dihydropyrimidinone derivatives containing imidazole moiety. J. Chem. 2019, 1−10. DOI:10.1155/2019/3131879.10.1155/2019/3131879
Search in Google Scholar Back to article

Facile synthesis and anticancer activity of novel dihydropyrimidinone derivatives

Abstract

Paradigm

My account