Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors

Kamal Sweidan; Dima A Sabbah; Sanaa Bardaweel; Khadeja Abu Dush; Ghassan Abu Sheikha; Mohammad S Mubarak

doi:10.1016/j.bmcl.2016.04.011

Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors

Bioorg Med Chem Lett. 2016 Jun 1;26(11):2685-90. doi: 10.1016/j.bmcl.2016.04.011. Epub 2016 Apr 6.

Authors

Kamal Sweidan¹, Dima A Sabbah², Sanaa Bardaweel³, Khadeja Abu Dush⁴, Ghassan Abu Sheikha⁵, Mohammad S Mubarak⁴

Affiliations

¹ Department of Chemistry, The University of Jordan, Amman 11942, Jordan. Electronic address: k.sweidan@ju.edu.jo.
² Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, PO Box 130, Amman 11733, Jordan. Electronic address: dima.sabbah@zuj.edu.jo.
³ Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.
⁴ Department of Chemistry, The University of Jordan, Amman 11942, Jordan.
⁵ Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, PO Box 130, Amman 11733, Jordan.

PMID: 27084677
DOI: 10.1016/j.bmcl.2016.04.011

Abstract

Structure-based drug design and molecular modeling were employed to identify a new series of indole-2-carboxamides as potential anticancer agents. These compounds were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectrometry as well as by elemental analysis. Molecular docking studies confirmed that the newly synthesized compounds accommodate PI3Kα and EGFR kinase catalytic sites and form H-bonding with the key binding residues. The antitumor activity of these new compounds against an array of cancer cell lines (human colon carcinoma (HCT116), leukemia (K562), and breast cancer (MDA231) was evaluated. Results revealed that these compounds were selective against the kinase domain, and none of them showed any inhibitory activity against K562. In addition, results showed that compound 13 exhibited high potency in HCT116 and MDA231 with IC50 values of 19 and 15μM, respectively. Our findings recommend that further optimization of this series would be beneficial for colon and breast cancer treatment.

Keywords: Docking; EGFR; HCT116; MDA231; PI3Kα.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Class I Phosphatidylinositol 3-Kinases
Computer-Aided Design*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Models, Molecular
Molecular Structure
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Indoles
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
ErbB Receptors