Nucleophilic reactions with the novel 7-(chromon-3-yl)quinolino [3′,4′:5,6] pyrano[3,2-c]quinoline: Synthesis, biological and computational studies

Abstract

Condensation reaction of 3-formylchromone (1) with 1-ethyl-4-hydroxyquinolin-2(1H)-one (2) in glacial acetic acid afforded the condensation product 4; in 1:2 molar ratio. Compound 4 was used as precursor for construction of some propenones linked pentacyclic quinolinopyranoquinoline. Ring opening of chromone moiety in compound 4 was achieved via reactions with a diversity of primary amines leading to propenone derivatives 5–7 and 11–13 in good yields (62–73%). All propanone derivatives exist in the E-configuration as deduced from their 1H NMR spectra. DFT/B3LYP functional was used with 6–311+G(d,p) basis sets for all theoretical calculations. Based on optimized geometry, the chemical potential (Pi), electronegativity (χ), hardness (η) and electrophilicity index (ω) are some of the global reactivity descriptors that were computed to predict the chemical reactivity of the studied compounds; where compound 13 has the highest softness and electrophilicity index (ω). Moreover, to determine the relative stability of compounds 1–4, the thermodynamic parameters such as enthalpy and free energies of the reactions were computed; where compound 4 has the lowest free energy of reaction (-439.61 kcal/mol), so its formation is spontaneous. By utilizing molecular electrostatic potential (MEP) and local-based descriptors in the form of condensed Fukui functions of the starting compound 4, the susceptible sites for electrophilic and nucleophilic attack were investigated. For compound 4, fk+ and Δfk values are more positive at C9 and C7 than other sites and these sites have more electrophilic characters. Therefore, nucleophilic attacks began at C9. On the other hand, the GIAO approximation was used to compute the 1H and 13C NMR chemical shift values in the ground state, of the present compounds, where a good agreement was observed between experimental and theoretical chemical shift results. Further, the calculated first hyperpolarizability of prepared compounds are found to be greater than that of urea. So, these compounds are ideal candidates for non-linear optical applications. The synthesized compounds were screened for their antimicrobial and anticancer activities showing variable inhibitory action. Compounds 5, 7 and 13 were more effective antimicrobial candidates against all tested microorganisms, while compound 13 was the most active against HepG-2 cell lines. Furthermore, a quantitative structure–activity relationship (QSAR) (relationship between DFT calculated descriptors and biological activities pIC50) model was built by applying multiple linear regression (MLR) on the synthesized compounds as anticancer agents. Moreover, Lipinski's rule of five indicates no problems with oral bioavailability of the prepared compounds.