Synthesis, characterization, DFT, QSAR, antimicrobial, and antitumor studies of some novel pyridopyrimidines

Abstract

6-Amino-5-formyluracil (1) was efficiently utilized for construction of a variety of novel heteroannulated pyrimidines. Friedländer condensation reaction of compound 1 with some cyclic active methylene ketones including 1,3-cyclohexanedione, dimedone, 1,3-indanedione, substituted pyrazolones, 1,3-thiazolidine-2,4-dione and thiobarbituric acid gave a variety of heterocycles fused pyrido[2,3-d]pyrimidines. Compound 1 reacted with some cyclic enamines such as 5-amino-3-methyl-1H-pyrazole, 6-aminouracil and 6-amino-1,3-dimethyluracil yielded pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine and pyrimido[5′,4′:5,6]pyrido[2,3-d]pyrimidines. In addition, reaction of compound 1 with some heterocyclic enols namely 4-hydroxycoumarin, 1-ethyl-4-hydroxyquinolin-2(1H)-one and 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one produced a diversity of polyfused systems. On the basis of DFT, the molecular structural parameters as well as a variety of global reactivity descriptors were calculated to inspect the optimized structures of the synthesized compounds. The values of energy gap of the present compounds ranging from 3.75- 4.82 eV; where compound 16 has the lowest value of energy barrier. To investigate for electrophilic and nucleophilic reactivity, the molecular electrostatic potential (MEP) of each molecule was measured. The synthesized compounds were screened in vitro for their bioassays against fungal strains, gram-positive and gram-negative bacteria, showing moderate and high inhibitory action. Also, most of the present compounds revealed good to excellent activities against colon carcinoma cell lines (HCT-116) and human Hepatocellular carcinoma cell lines (HePG-2). Compounds 5 and 10-12 showed higher antiproliferative activity (from 2.68 to 16.82 µg/mL) against the two types of cancer cell lines as compared with the reference drug (5-fluoeouracil). Quantitative structure activity relationship (QSAR models) were created using a multiple linear regression analysis (MLR) procedures and were used to design the correlations between molecular descriptors and antitumor activity of the prepared compounds.