Oxazoles as potential anticancer agents: synthesis, in vitro, in silico studies and structure-activity relationship

Abstract

A series of 4-unsubstituted, 4-phosphorylated, and 4-cyano-substituted 1,3-oxazoles was evaluated for anticancer screening. Compounds with acceptor substituents in the positions 4 and 5 of azole ring inhibit the growth of a series of NCI-60 panel cancer cell lines, and compounds with donor -SR substituents and -H in the position 5 do not practically inhibit the growth of cancer lines. The quantum‐chemical modeling of model and synthesized oxazole molecules was performed to study steric and electronic properties that may determine the manifestation of anticancer activity. The donor/acceptor properties of 1,3‐oxazoles were evaluated using parameter φ0, which takes into account the relative position of the HOMO and LUMO levels. In silico evaluating of the binding energies of three 1,3-oxazoles to the orthosteric sites of receptors CB2 and A3AR was estimated, and the contribution of different types of substrate-biomolecule interactions was assessed. Calculations show a significant change in the φ0 value upon replacement of the donor substituent at position 5 of the oxazole with hydrogen and the acceptor sulfinyl or sulfonyl substituents. This correlates with the corresponding change in bioactivity, which increases upon substitution from donor to acceptor group at position 5 of the oxazoles. The obtained in silico and in vitro results of the compounds activity proved the perspective of further study of oxazoles as effective anticancer agents