Design, synthesis, molecular docking and in silico ADMET profile of pyrano[2,3-d]pyrimidine derivatives as antimicrobial and anticancer agents

• Published in: Bioorganic chemistry 2021-10, Vol.115, p.105186-105186, Article 105186
• Main Authors: Abd El-Sattar, Nour E.A., El‐Adl, Khaled, El-Hashash, Maher A., Salama, Samir A., Elhady, Mostafa M.
• Format: Article
• Language: English
• Subjects: Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antimicrobial; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Barbituric acid; Cytotoxic activities; DNA intercalators; Drug Design; Escherichia coli - drug effects; Fungi - drug effects; Gram-Positive Bacterial Infections - drug therapy; HCT116 Cells; Hep G2 Cells; Humans; MCF-7 Cells; Molecular Docking Simulation; Mycoses - drug therapy; Neoplasms - drug therapy; Pyranopyrimidine derivatives; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Staphylococcus aureus - drug effects
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105186

[Display omitted] •Eleven novel pyrano[2, 3-d]pyrimidine derivatives were designed and synthesized.•Antimicrobial activities were evaluated against gram positive, gram negative bacteria and fungi.•Cytotoxic activities were evaluated against three human cell lines HepG2, HCT-116 and MCF-7.•In vitro DNA-binding and Topo II enzyme inhibition assay were carried out for the most active derivatives.•Molecular docking studies were carried out. Pyrano[2,3-d]pyrimidine derivatives were synthesized by treating cyclic compounds containing active methylene group with aldehyde and malononitrile in butanol. The behavior of pyrano[2,3-d]pyrimidine towards some electrophlies namely triethylorthoformate followed by nitrogen nucleophiles as isobutylamine, urea, phenylthiourea, p-toluidine, o-phenylenediamine, o-aminophenol, 2-amino-4-methyl-pyridine and acetic acid with the aim of obtaining some interesting non-mixed heterocyclic compounds. All synthesized compounds to some extent have shown good antimicrobial activity against different microbial strains that had been extracted by inhibiting cell wall synthesis. Compound 5b showed the highest antibacterial activities against B. subtilis, S. aureus and E. coli. On the other hand compound 5 g exhibited the highest antibacterial and antifungal activities against P. aeruginosa and A. niger respectively. In addition, they explore cytotoxic potentialities against different cell lines via DNA intercalation and Top-II inhibition. The cytotoxic activities clarify the strong inhibitory activity of derivative 5a against HepG2 cells with IC50 = 2.09 μM, while HCT-116 cells were highly susceptible to derivative 5c with IC50 = 2.61 μM, in the meantime, derivative 5f showed pronounced negative impact against MCF-7 (IC50 = 2.43 μM) when compared with other prepared compounds. All derivatives exhibited higher anticancer activities than doxorubicin against the three cell lines except compound 2 against both HepG2 and MCF-7 and compound 5e against HepG2 cell lines. Compounds 5a, 5c and 5f potently intercalate DNA at IC50 values of 26.96, 27.13 and 29.86 µM respectively, which were more potent than doxorubicin (IC50 value of 31.27 µM). Moreover, compounds 5a, 5c and 5f exhibited very good Topoisomerase II inhibitory activities with IC50 values of 0.752, 0.791 and 0.776 µM respectively, that were more potent than that of doxorubicin (IC50 = 0.94 µM). For a great extent, the molecular modeling studies were in agreement with that of in vitro cyto