Targeted synthesis of new 4-imidazolinone derivatives and evaluation of their anticancer activity

Aim: To perform new 4-imidazolinone compounds modeling and based on in silico results select the most potential compounds for synthesis, physico-chemical analysis and anticancer activity evaluation. Objectives: 1) To perform in silico modeling of new compounds and select the most potential compounds for synthesis. 2) Perform targeted synthesis of new 4-imidazolinone derivatives, determine their structure and purity. 3) To perform preliminary anticancer activity evaluation of synthesized compounds. 4) To determine correlation of in silico and in vitro experimental results. Methods: Ligand modeling and in silico evaluation was performed using “Schrӧdinger 2014-2: small molecule drug discovery suite” software. Purity of synthesized compounds was determined using HPLC and TLC methods. The identity of compounds was confirmed by UV and IR spectroscopy. Compounds anticancer activity evaluation was performed using XTT cell proliferation essay. Results: After in silico molecule modeling and ligand evaluation 45 compounds with favorable pharmacokinetic properties (e.g. logP between -0.4 and +5.6, predicted oral absorbtion >60%) and possible anticancer activity were selected for synthesis. Docking results analysis showed that predicted activity increases when ligand contains 4-fluorobenzaldehyde, 5-(substituted aryl)-2-furfuralaldehydes in 5th position and 4-phenoxyaniline, 4-aminosalicylic acid, 4-aminobenzoic acid in 2nd position of 4-imidazolinone ring. 14 new compounds were successfully sinthesized, their structure and purity were determined. HPLC analysis lead to identify 11 compounds with high purity level (>90%) that was suitable for anticancer activity evaluation using XTT cell proliferation assay. Preliminary anticancer activity evaluation showed that the most active compounds contained 4-phenoxyaniline in 2nd position of 4-imidazolinone ring. The most active compound was HAM10-6 that inhibited metabolic activity of 90.33±15.43% cells in the sample (p<0.01). Conclusions: After in silico virtual screening of 5097 ligands, 14 new 4-imidazolinone compounds targeting Bcl-2 were successfully synthesized. Compound interaction energy ΔE varying between -4.274 and -6.725 kcal/mol towards Bcl-2 protein. Determined compound purity level varying between 72.57% and 98.97%. Preliminary anticancer activity evaluation showed 8 compounds with possible anticancer activity that inhibited metabolic activity of more than 50% cells (p