Benzimidazole-dioxoisoindoline conjugates as dual VEGFR-2 and FGFR-1 inhibitors: design, synthesis, biological investigation, molecular docking studies and ADME predictions

Abstract

In this investigation, a new series of benzimidazole-dioxo(benzo)isoindoline hybrids 8a-o were rationally designed and synthesized. All the synthesized hits 8a-o were investigated for their VEGFR-2 inhibitory activity at 10 μM. The conjugates 8l and 8m demonstrated potent inhibitory activity of 87.61 and 80.69%, respectively. Further evaluation of 8l and 8m on FGFR-1 at 10 μM demonstrated % inhibition = 84.20 and 76.83%, respectively. Investigation of the growth inhibitory activity of the synthesized hits on NCI cancer cell lines showed that the benzimidazole-dioxobenzoisoindoline hybrid 8m exhibits the highest antiproliferative activity. It displayed growth inhibitory activity reaching 89.75%. Examination of the effect of 8m on the cell cycle of MCF7 cell line revealed its ability to induce arrest of the cell cycle at the G2/M phase and its potential to induce the apoptosis of the same cell line. Additionally, the benzimidazole-dioxobenzoisoindoline hybrid 8m had potent anti-migratory properties as evidenced by the delay in the wound closure in reference to untreated control cells. Molecular docking of 8m in the binding pockets of the VEGFR-2 and FGFR-1 proved its ability to occupy the binding pockets of both targets in type II inhibitor binding mode and to perform the essential interactions with the crucial amino acids in the binding pockets of both targets. Moreover, ADME prediction studies demonstrated the drug like properties of the synthesized benzimidazole-dioxoisoindolines 8a-o.

Fig. 1. Benzimidazole-based multi-kinase inhibitors.

Fig. 2. Suggested strategy for the design of benzimidazole–dioxo(benzo)isoindoline conjugates VI.

Scheme 1. Pathway for the synthesis of the benzimidazole–dioxo(benzo)isoindolines 8a–o.

Fig. 3. Structure–activity relationship of the benzimidazoles–dioxo(benzo)isoindoline conjugates 8a–o on the inhibition percentage of VEGFR-2.

Fig. 4. Compound 8m's effect on MCF-7 cells' cell cycle stages.

Fig. 5. Effect of 8m on the percentage of annexin V-FITC-positive staining in MCF-7 cell line, the four quadrants are: Q2-1 (necrotic), Q2-2 (late apoptotic), Q2-3 (viable); Q2-4 (early apoptotic).

Fig. 6. Daily measurement of the wound distances of MCF-7 cell line before and after treatment with 8m.

Fig. 7. 3D presentation of 8m in the binding site of VEGFR-2.

Fig. 8. 3D presentation of 8m in the binding site of FGFR-1.

Fig. 9. Bioavailability radar chart from SwissADME free web tool of 8l and 8m.