Synthesis of 2-phenyl- and 2-benzyl derivatives of 4(3Н)-quinazolinone with analgesic activity

Quinazolin-4(3Н)-one derivatives are characterized by a wide range of pharmacological properties, among which the most significant one is a pronounced effect on the central nervous system. In this regard, a molecular design of biologically active compounds that have an analgesic activity due to the formation of ligand-receptor complexes with nociceptive and dopamine receptors, has been performed.

The aim of the study was a molecular design and a subsequent targeted synthesis of 2-phenyl- and 2-benzyl derivatives of 4(3H)-quinazolinone with an analgesic activity, as well as the creation of a mathematical model in order to identify significant molecular descriptors.

Materials and methods. A molecular design was carried out by a logical-structural approach using the PASS program with the identification of the biological activity of the predicted structures, as well as the energy calculation of the ligand-receptor interaction. The synthesis of 2-phenyl derivatives of 4(3H)-quinazolinone was carried out by the reaction of 2-aminobenzamide with aromatic aldehydes in polyphosphoric acid when heated, while the 2-benzyl derivatives were synthesized by fusing amides of anthranilic and homoveratric acids followed by sulfonation with sulfuric acid. The analgesic activity of the synthesized compounds was studied in the models of nociceptive reactions induced by chemical stimuli (a formalin test and “acetic acid writhings”).

Results. A molecular design made it possible to identify promising structures in the series of 4(3H)-quinazolinone derivatives that affect nociceptive and dopamine receptors and have an analgesic activity. A modification was made to the synthesis of 2-phenyl- and 2-benzyl derivatives of 4(3H)-quinazolinone in order to increase the yield of the target products by a simpler and more cost-effective method. The predicted compounds were synthesized by cyclocondensation of anthranilic acid amide with aromatic aldehydes or with homoveraic acid amide. It follows from the primary pharmacological studies results that the synthesized substances are promising from the point of view of creating painkillers based on them. A structure-activity relationship between the molecular descriptors, which are largely responsible for the analgesic activity, and the results of biological tests, has been revealed.

Conclusion. The use of computer modelling made it possible to identify the amino acid residues involved in the formation of the ligand-receptor complex with the nociceptive receptor, and to construct a mathematical model to explain the analgesic activity of 2-phenyl- and 2-benzyl derivatives of 4(3H)-quinazolinone. Modified procedures for the synthesis of target compounds have been proposed. The obtained coefficients of the approximation between the theoretical values and the data of the pharmacological experiment make it possible to state a sufficient reliability of the carried out studies.