Synthesis, In Silico Prediction and In Vitro Evaluation of Antitumor Activities of Novel Pyrido[2,3-d]pyrimidine, Xanthine and Lumazine Derivatives

Abstract

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.

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein

“…The substituted 6-aminouracil derivatives 2a – e were obtained by adding urea, methyl urea, and/or methyl thiourea to ethyl cyanoacetate in absolute ethanol containing sodium (sodium ethoxide) by heating under reflux, according to the reported methods [ 21 , 22 ]. Additionally, 5-(substituted-sulfonyl)indoline-2,3-dione 1a – c were prepared according to the previously reported method [ 23 , 24 ].…”

Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors

“…As shown in Scheme 2 , the variable 5,6-diaminouracil/thiouracil derivatives 9a–e were prepared via consecutive cyclization of N -alkylurea/thiourea with ethyl cyanoacetate in the presence of sodium ethoxide, which initially gave 6-aminouracil/thiouracils 7a – e . This was readily followed by conversion via a nitrosation process using nitrous acid and then reduction of nitroso uracil/thiouracils 8 a– e via the reducing agent ammonium sulfide [ 80 , 81 ].…”

“…All starting materials and reagents were generally commercially available and purchased from Sigma-Aldrich or Lancaster Synthesis Corporation (Lancaster, UK). Compounds 4a–c and 9a–e were prepared according to the reported method [ 80 , 81 , 94 , 95 , 96 ].…”

Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives

“…Here, we reported the synthesis of novel purine derivatives and the assessment of their antibacterial and antifungal activities. 5,6-Diaminouracils 1a-e, the key starting material for the obtained compounds, were synthesized by the reaction between ethyl cyanoacetate and different urea derivatives followed by nitrosation and reduction by conventional methods [25,38,39]. The Erlenmeyer azlactones (2a-c), also known as 4-arylideno-5(4H)-1,3-oxazolones, were synthesized according to literature [40][41][42][43] through an aldol-type condensation of a glycine-based azlactone (A) with different aldehydes (Scheme 2).…”

“…Synthetic Procedures 5,6-diaminouracils 1a-e. These compounds were prepared according to a reported method [25,38,39]. 4-arylideno-5(4H)-1,3-oxazolones (2a-c) These compounds were prepared according to a reported method [40][41][42][43].…”