Discovery of Rhodanine and Thiazolidinediones as Novel Scaffolds for EGFR Inhibition: Design, Synthesis, Analysis and CoMSIA Studies

Abstract

This study reports, 35 novel rhodanine, its bioisosteres thiazolidinediones and is tested for EGFR inhibition. These molecules are designed by using a pharmacophore-based superimpose approach taking Gefitinib as a core structure or reference. All the designed molecules were synthesized from 3-chloro and 4-fluoro substituted aniline as the precursors and converted to corresponding dithiocarbamate (3a, b) by reacting with carbon disulfide in presence of ammonia. Further, it was cyclized to rhodanine (4a, b) and subjected to Knoevenagel condensation to find compounds 5(a-j) and 6(a-i). All the compounds are analyzed and from the NMR results, we found that Knoevenagel condensed products are of “Z” geometrical isomers. Further, rhodanine was converted to its bioisosteric form thiazolidinedione by reacting it with a catalytic amount of diacetoxy-iodobenzene in presence of alcohol. All the synthesized compounds are characterized by IR, ¹H NMR, ¹³C NMR, and Mass analysis, and screened for their EGFR inhibition, among all the synthesized compounds, compound 5i, 6 h, 7c, and 8f showed promising results by inhibiting EGFR at <10 nM. Further, structure-activity relationships were established via CoMSIA studies.

A series of 35 novel rhodanine, its bioisosteres thiazolidinediones were synthesized by taking 4-fluoro and 3-chloro aniline as a precursors and different aldehydes via Knoevenagel condensation. The synthesized compounds were subjected to In vitro EGFR assay. All the compounds showed a comparable biological activity compared to the standard drug. Additionally, molecular docking and CoMSIA study were performed to support the hypothesis.

Keywords:

• CoMSIA studies
• docking
• EGFR inhibition
• rhodanine
• thiazolidinedione

Acknowledgments

The authors are thankful to the management of JSS College of Pharmacy for extending the necessary facilities to perform this multidisciplinary research. The authors also express gratitude to the Director, NMR research centre, Indian Institute of Science, Bangalore for spectral data.

Disclosure statement

There are no conflicts of interest among the authors.