Ethyl 5-arylpyridopyrimidine-6-carboxylates 3a–d were prepared as a one pot three component reaction via the condensation of different aromatic aldehydes and ethyl acetoacetate with 6-amino-1-benzyluracil 1a under reflux condition in ethanol. Additionally, condensation of ethyl 2-(2-hydroxybenzylidene) acetoacetate with 6-amino-1-benzyluracil in DMF afforded 6-acetylpyridopyrimidine-7-one 3e; a facile, operationally, simple and efficient one-pot synthesis of 8-arylxanthines 6a–f is reported by refluxing 5,6-diaminouracil 4 with aromatic aldehydes in DMF. Moreover, 6-aryllumazines 7a–d was obtained via the reaction of 5,6-diaminouracil with the appropriate aromatic aldehydes in triethyl orthoformate under reflux condition. The synthesized compounds were characterized by spectral (1H-NMR, 13C-NMR, IR and mass spectra) and elemental analyses. The newly synthesized compounds were screened for their anticancer activity against lung cancer A549 cell line. Furthermore, a molecular-docking study was employed to determine the possible mode of action of the synthesized compounds against a group of proteins highly implicated in cancer progression, especially lung cancer. Docking results showed that compounds 3b, 6c, 6d, 6e, 7c and 7d were the best potential docked compounds against most of the tested proteins, especially CDK2, Jak2, and DHFR proteins. These results are in agreement with cytotoxicity results, which shed a light on the promising activity of these novel six heterocyclic derivatives for further investigation as potential chemotherapeutics.

Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained by cyclocondensation of 5,6-diaminouracils 1a-c with different oxazolones in glacial acetic acid. Moreover, 5, 6-diaminouracils 1a-e were reacted with oxazolones 2a-c in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives 6-13. Furthermore, Schiff base of compounds 14-16 were obtained by condensing 5, 6-diaminouracils 1a,b,e with 4-dimethylaminobenzaldehyde in acetic acid. The structural identity of the resulting compounds was resolved by IR, 1H-, 13C-NMR and Mass spectral analyses. The novel synthesized compounds were screened for their antifungal and antibacterial activities. Compounds 3, 6, 13 and 16 displayed the highest activity against Escherichia coli as revealed from the IC50 values (1.8–1.9 µg/mL). The compound 16 displayed a significant antifungal activity against Candia albicans (0.82 µg/mL), Aspergillus flavus (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds 3, 12, 13 and 16 exhibited a strong deformation to the cellular entities, by interfering with the cell membrane components, causing cytosol leakage, cellular shrinkage and irregularity to the cell shape. In addition, docking study for the most promising antimicrobial tested compounds depicted high binding affinity against acyl carrier protein domain from a fungal type I polyketide synthase (ACP), and Baumannii penicillin- binding protein (PBP). Moreover, compound 12 showed high drug- likeness, and excellent pharmacokinetics, which needs to be in focus for further antimicrobial drug development. The most promising antimicrobial compounds underwent theoretical investigation using DFT calculation.

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Abstract:A variety of different compounds of fused uracils were prepared simply by the heating of 6-hydrazinyl-1-methyl-, 6-hydrazinyl-1-propyl-, or 6-hydrazinyl-1,3-dipropyluracil under reflux with ninhydrin, isatin, benzylidene malononitrile, benzylylidene ethyl cyanoacetate, benzil, and phenacyl bromide derivatives. The newly synthesized compounds were completely screened for antimicrobial and antitumor activity.

A novel and efficient route towards the synthesis of pyrido [2,3d:6,5-d']dipyrimidines 4 a-g as unexpected products through the reaction of 6-aminouracil (1) and arylidenemalononitrile or ethyl arylidenecyanoacetate in acetic acid were investigated. On the other hand, reaction of 6-aminouracil and ethyl 4nitrobenzylidenecyanoacetate in ethanol in presence of piperidine (few drops) afforded pyrido[2,3-d]pyrimidine-6-carbonitrile 5. In addition, pyrido[2,3-d]pyrimidines 6 a-g were obtained through the reaction of 5 with different aliphatic amines in ethanol in presence of triethylamine (few drops). All reactions proceeded in good to excellent yields and the resulting compounds were characterized by different spectroscopic techniques. The antiproliferative activity of these compounds was evaluated towards HEPG-2, MCF-7 and HCT-116 cell lines. The compound 6 a displayed the highest activity against the tested cell lines, followed by compound 6 d, 6 g and 6 b, with strong affinity to bind with the active and allosteric sites of topoisomerase II, as authenticated from the molecular docking analyses.