Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives

Title:Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives

Volume: 17 Issue: 5

Author(s): Oluwole S. Aremu, Kaalin Gopaul, Pramod Kadam, Moganavelli Singh, Chunderika Mocktar, Parvesh Singh and Neil A. Koorbanally*

Affiliation:

• School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000,south africa

Keywords: Pyranopyrimidinedione, malononitrile, barbituric acid, DABCO, MRSA, antibacterial activity.

Abstract: Background: Pyrimidines have widespread activity and have shown potent antibacterial and anticancer activity.

Objective: To synthesise a range of pyrimidine diones and test them for their antibacterial and anticancer activity.

Method: The pyranopyrimidin-2,4-dione derivatives (1-7) were synthesized in a one-pot reaction by reacting malononitrile and barbituric acid with several aromatic aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in aqueous medium. The compounds were tested for their antibacterial activity using the broth microdilution method and for their cytotoxicity against three cell lines, HeLa (cervical cancer), Caco-2 (human colon adenocarcinoma) and HEK 293 (human embryonic kidney cells) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay.

Results: Compounds 1-7 were successfully synthesized in yields of >90%. The 3,4-dihydroxyaryl (3) and the 2,5- dimethoxyaryl (7) derivatives were novel. Compounds 3, 5 (4'-methoxy derivative) and 6 (2',3'-dimethoxy derivative) showed antibacterial activity comparable to or better than the standard ampicillin. All the test compounds 1-7 showed good anticancer activity. The IC50 values ranged from 3.46 to 37.13 μM (HeLa); 136.78 to 297.05 μM (Caco-2) and 137.84 to 333.81 μM (HEK293). The best activity was seen in the HeLa cell line when compared to the standard 5FU (5-Fluorouracil IC50 of 41.85 μM), with 1, 2, 5 and 7 having IC50 values of 10.64, 3.46, 4.36 and 4.44 μM respectively. Additionally, two representative compounds (1 and 7) found to be potent against the two cell lines (HeLa and HEK 293) were docked into the binding site of human kinesin Eg5 with the aim of predicting their binding propensities and to establish their mechanism of action. The Lipinski parameters of these compounds were also computed and analysed for their drug-likeness.

Conclusion: Compound 6 is an excellent candidate for a broad spectrum antibiotic with MBCs of 45.6-365.2 μM, while both 3 and 6 have the potential to be developed into an antibiotic against MRSA, with MBCs of 183-199 μM. Since all synthesized compounds showed IC50 values of 10 μM or less especially against the HeLa cells, they can be considered good lead compounds for anticancer agents. Additionally, the docking simulations suggested a good binding affinity of the compounds with Eg5 and indicated their anti-cancer action, at least partially, through its inhibition. The predicted Lipinski descriptors also indicated the potential of these compounds as an orally active drug.

Cite this article as:

Aremu S. Oluwole, Gopaul Kaalin, Kadam Pramod, Singh Moganavelli, Mocktar Chunderika, Singh Parvesh and Koorbanally A. Neil*, Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives, Anti-Cancer Agents in Medicinal Chemistry 2017; 17 (5) . https://dx.doi.org/10.2174/1871520616666160813213245

DOI https://dx.doi.org/10.2174/1871520616666160813213245	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992