Pyrimidines-Based Heterocyclic Compounds: Synthesis, Cytoxicity Evaluation and Molecular Docking

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Aug 12

PMID 35956864

Authors

Mohamed A El-Atawy

Najla A Alshaye

Nada Elrubi

Ezzat A Hamed

Alaa Z Omar

Affiliations

Soon will be listed here.

Abstract

A variety of structurally different pyrimidines were synthesized. Elemental analysis, FT-IR, H NMR, and C NMR spectroscopy were used to confirm the chemical structures of all prepared compounds. The synthesized pyrimidines were screened against the growth of five human cancer cell lines (prostate carcinoma PC3, liver carcinoma HepG-2, human colon cancer HCT-116, human breast cancer MCF-7, human lung cancer A-549), and normal human lung fibroblasts (MRC-5) using MTT assay. Most of the screened pyrimidines have anti-proliferative activity on the growth of the PC3 cell line. Compounds and were more potent than the reference vinblastine sulfate (~2 to 3 × fold) and they can be considered promising leads for treating prostate cancer disease. Moreover, the screened compounds , , , , and were assessed according to the values of their selectivity index (SI) and were found to be more selective and safer than vinblastine sulfate. Furthermore, using in silico computational tools, the physicochemical properties of all pyrimidine ligands were assessed, and the synthesized compounds fall within the criteria of RO5, thus having the potential to be orally bioavailable.

Citing Articles

Synthesis, DFT, and biological evaluation of chalcone bearing pyrazoline ring against receptors.

Alshaye N, Alharbi N, El-Atawy M, El-Zawawy R, Hamed E, Elhag M Heliyon. 2024; 10(14):e34540.

PMID: 39130476 PMC: 11315094. DOI: 10.1016/j.heliyon.2024.e34540.

Design, Synthesis, Characterization, and Cytotoxicity of New Pyrazolylmethylene-2-thioxoimidazolidin-4-one Derivatives towards Androgen-Sensitive LNCaP Prostate Cancer Cells.

El-Atawy M, Kebeish R, Almotairy A, Omar A Biomolecules. 2024; 14(7).

PMID: 39062524 PMC: 11274643. DOI: 10.3390/biom14070811.

Design, synthesis, studies and apoptotic activity of novel amide enriched 2-(1)- quinazolinone derivatives.

Gariganti N, Bandi A, Gatta K, Pagag J, Guruprasad L, Poola B Heliyon. 2024; 10(9):e30292.

PMID: 38711664 PMC: 11070864. DOI: 10.1016/j.heliyon.2024.e30292.

Design, Synthesis and Biological Assessment of '-(2-Oxoindolin-3-ylidene)-6-methylimidazo[2,1-]thiazole-5-carbohydrazides as Potential Anti-Proliferative Agents toward MCF-7 Breast Cancer.

Alshaye N, Elgohary M, Elkotamy M, Abdel-Aziz H Pharmaceuticals (Basel). 2024; 17(2).

PMID: 38399431 PMC: 10892120. DOI: 10.3390/ph17020216.

Synthesis, Characterization, Antioxidant, and Anticancer Activity against Colon Cancer Cells of Some Cinnamaldehyde-Based Chalcone Derivatives.

El-Atawy M, Hanna D, Bashal A, Ahmed H, Alshammari E, Hamed E Biomolecules. 2024; 14(2).

PMID: 38397453 PMC: 10886690. DOI: 10.3390/biom14020216.

References

Ali K, Ragab E, Farghaly T, Abdalla M . Synthesis of new functionalized 3-substituted [1,2,4]triazolo [4,3-a]pyrimidine derivatives: potential antihypertensive agents. Acta Pol Pharm. 2011; 68(2):237-47. View

Ettridge K, Bowden J, Chambers S, Smith D, Murphy M, Evans S . "Prostate cancer is far more hidden…": Perceptions of stigma, social isolation and help-seeking among men with prostate cancer. Eur J Cancer Care (Engl). 2017; 27(2):e12790. DOI: 10.1111/ecc.12790. View

Ramirez-Macias I, Maldonado C, Marin C, Olmo F, Gutierrez-Sanchez R, Rosales M . In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis. J Inorg Biochem. 2012; 112:1-9. DOI: 10.1016/j.jinorgbio.2012.02.025. View

Lotinun S, Sibonga J, Turner R . Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism. Endocrinology. 2003; 144(5):2000-7. DOI: 10.1210/en.2002-221000. View

Msaouel P, Pissimissis N, Halapas A, Koutsilieris M . Mechanisms of bone metastasis in prostate cancer: clinical implications. Best Pract Res Clin Endocrinol Metab. 2008; 22(2):341-55. DOI: 10.1016/j.beem.2008.01.011. View

Zhang H, Wang J, Zhao H, Yang X, Lei H, Xin M . Synthesis and biological evaluation of irreversible EGFR tyrosine kinase inhibitors containing pyrido[3,4-d]pyrimidine scaffold. Bioorg Med Chem. 2018; 26(12):3619-3633. DOI: 10.1016/j.bmc.2018.05.039. View

Guan L, Sui X, Chang Y, Yan Z, Tong G, Qu Y . Design, synthesis and anticonvulsant activity evaluation of 7-substituted-[1,2,4]-triazolo[4,3-f]pyrimidine derivatives. Med Chem. 2012; 8(6):1076-83. DOI: 10.2174/1573406411208061076. View

Zuniga E, Korkegian A, Mullen S, Hembre E, Ornstein P, Cortez G . The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents. Bioorg Med Chem. 2017; 25(15):3922-3946. PMC: 5513444. DOI: 10.1016/j.bmc.2017.05.030. View

Chen Q, Zhu X, Jiang L, Liu Z, Yang G . Synthesis, antifungal activity and CoMFA analysis of novel 1,2,4-triazolo[1,5-a]pyrimidine derivatives. Eur J Med Chem. 2007; 43(3):595-603. DOI: 10.1016/j.ejmech.2007.04.021. View

10.

Omar A, Alshaye N, Mosa T, El-Sadany S, Hamed E, El-Atawy M . Synthesis and Antimicrobial Activity Screening of Piperazines Bearing ,-Bis(1,3,4-thiadiazole) Moiety as Probable Enoyl-ACP Reductase Inhibitors. Molecules. 2022; 27(12). PMC: 9228617. DOI: 10.3390/molecules27123698. View

11.

Tian C, Chen X, Zhang Z, Wang X, Liu J . Design and synthesis of (2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone analogues as potent anti-tubulin polymerization agents. Eur J Med Chem. 2019; 183:111679. DOI: 10.1016/j.ejmech.2019.111679. View

12.

Long L, Luo Y, Hou Z, Ma H, Long Z, Tu Z . Synthesis and biological evaluation of aurora kinases inhibitors based on N-trisubstituted pyrimidine scaffold. Eur J Med Chem. 2018; 145:805-812. DOI: 10.1016/j.ejmech.2017.12.082. View

13.

Li S, Guo C, Zhao H, Tang Y, Lan M . Synthesis and biological evaluation of 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-substituted-phenoxy)pyrimidines as dual EGFR/ErbB-2 kinase inhibitors. Bioorg Med Chem. 2011; 20(2):877-85. DOI: 10.1016/j.bmc.2011.11.056. View

14.

Liu Y, Xia Q, Fang L . Design and synthesis of alkyl substituted pyridino[2,3-D]pyrimidine compounds as PI3Kα/mTOR dual inhibitors with improved pharmacokinetic properties and potent in vivo antitumor activity. Bioorg Med Chem. 2018; 26(14):3992-4000. DOI: 10.1016/j.bmc.2018.06.025. View

15.

Singla P, Luxami V, Singh R, Tandon V, Paul K . Novel pyrazolo[3,4-d]pyrimidine with 4-(1H-benzimidazol-2-yl)-phenylamine as broad spectrum anticancer agents: Synthesis, cell based assay, topoisomerase inhibition, DNA intercalation and bovine serum albumin studies. Eur J Med Chem. 2016; 126:24-35. DOI: 10.1016/j.ejmech.2016.09.093. View

16.

Yang F, Yu L, Diao P, Jian X, Zhou M, Jiang C . Novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potent antitubulin agents: Design, multicomponent synthesis and antiproliferative activities. Bioorg Chem. 2019; 92:103260. DOI: 10.1016/j.bioorg.2019.103260. View

17.

Li J, Gu W, Bi X, Li H, Liao C, Liu C . Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors. Bioorg Med Chem. 2017; 25(24):6674-6679. DOI: 10.1016/j.bmc.2017.11.010. View

18.

Ibrahim M, Abou-Seri S, Hanna M, Abdalla M, El Sayed N . Design, synthesis and biological evaluation of novel condensed pyrrolo[1,2-c]pyrimidines featuring morpholine moiety as PI3Kα inhibitors. Eur J Med Chem. 2015; 99:1-13. DOI: 10.1016/j.ejmech.2015.05.036. View

19.

Beer T, Armstrong A, Rathkopf D, Loriot Y, Sternberg C, Higano C . Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371(5):424-33. PMC: 4418931. DOI: 10.1056/NEJMoa1405095. View

20.

Nettekoven M, Adam J, Bendels S, Bissantz C, Fingerle J, Grether U . Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases. ChemMedChem. 2015; 11(2):179-89. DOI: 10.1002/cmdc.201500218. View