A novel class of phenylpyrazolone-sulphonamides rigid synthetic anticancer molecules selectively inhibit the isoform IX of carbonic anhydrases guided by molecular docking and orbital analyses

All the previously reported phenylpyrazoles as carbonic anhydrase inhibitors (CAIs) were found to have small sizes and high levels of flexibility, and hence showed low selectivity profiles toward a particular isoform of CA. Herein, we report the development of a more rigid ring system bearing a sulfonamide hydrophilic head and a lipophilic tail to develop novel molecules that are suggested to have a better selectivity toward a special CA isoform. Accordingly, three novel sets of pyrano[2,3-c]pyrazoles attached with sulfonamide head and aryl hydrophobic tail were synthesized to enhance the selectivity toward a specific isoform of human carbonic anhydrases (hCAs). The impact of both attachments on the potency and selectivity has been extensively discussed in terms of in vitro cytotoxicity evaluation under hypoxic conditions, structure-activity relationship and carbonic anhydrase enzyme assay. All of the new candidates displayed good cytotoxic activities against breast and colorectal carcinomas. Results of the carbonic anhydrase enzyme assay demonstrated the preferential of compounds 22, 24 and 27 to inhibit the isoform IX of hCAs selectively. Wound-healing assay has also been performed and revealed the potential of 27 to decrease the wound closure percentage in MCF-7 cells. Molecular docking and molecular orbital analysis have finally been conducted. Results indicate the potential binding interactions of 24 and 27 with several crucial amino acids of the hCA IX.Communicated by Ramaswamy H. Sarma

Automated summary

This study developed a more rigid ring system with a sulfonamide hydrophilic head and a lipophilic tail to synthesize novel molecules with better selectivity. The activity and selectivity of these molecules were extensively discussed through in vitro cytotoxicity evaluation, structure-activity relationship, and carbonic anhydrase enzyme assay. The results showed that all the new candidates exhibited good cytotoxic activities against breast and colorectal carcinomas, with compounds 22, 24, and 27 selectively inhibiting hCA IX. Furthermore, compound 27 demonstrated the potential to decrease the wound closure percentage in MCF-7 cells. Molecular docking and molecular orbital analysis revealed the potential binding interactions of compounds 24 and 27 with crucial amino acids of hCA IX.