title: Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Oluwole S
authors.initials: OS
authors.lastname: Aremu
authors.forename: Kaalin
authors.initials: K
authors.lastname: Gopaul
authors.forename: Pramod
authors.initials: P
authors.lastname: Kadam
authors.forename: Moganavelli
authors.initials: M
authors.lastname: Singh
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, South Africa.
authors.forename: Chunderika
authors.initials: C
authors.lastname: Mocktar
authors.forename: Parvesh
authors.initials: P
authors.lastname: Singh
authors.affiliation: School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, South Africa.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Koorbanally
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D011744:Pyrimidinones
keywords: DABCO; MRSA; Pyranopyrimidinedione; antibacterial activity; barbituric acid; malononitrile