Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents

Title:Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents

Volume: 18 Issue: 2

Author(s): Dima A. Sabbah*, Bayan Hishmah, Kamal Sweidan, Sanaa Bardaweel, Murad AlDamen, Haizhen A. Zhong, Reema Abu Khalaf, Ameerah (Hasan Ibrahim), Tariq Al-Qirim, Ghassan Abu Sheikha and Mohammad S. Mubarak

Affiliation:

• Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman 11733,Jordan

Keywords: Cytotoxicity, HCT-116, apoptosis, LDH, docking, quinolone-3-carboxamide.

Abstract: Background: Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has been highlighted as a therapeutic target for anticancer drug design.

Objective: Target compounds were designed to address the effect of different substitution patterns at the N atom of the carboxamide moiety on the bioactivity of this series.

Methods: Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon carcinoma (HCT-116), and Glide docking studies.

Results: A new series of N-substituted- 4-hydroxy-2-quinolone-3-carboxamides was prepared and characterized by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising PI3Kα inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and 18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kα and caspase-3 showed an agreement between the predicted binding affinity (ΔGobsd) and IC50 values of the derivatives for the caspase-3 model. Furthermore, Glide docking studies against PI3Kα demonstrated that the newly synthesized compounds accommodate PI3Kα kinase catalytic domain and form H-bonding with key binding residues.

Conclusion: The series exhibited a potential PI3Kα inhibitory activity in HCT-116 cell line.

Cite this article as:

Sabbah A. Dima*, Hishmah Bayan, Sweidan Kamal, Bardaweel Sanaa, AlDamen Murad, Zhong A. Haizhen , Abu Khalaf Reema, (Hasan Ibrahim) Ameerah , Al-Qirim Tariq, Abu Sheikha Ghassan and Mubarak S. Mohammad, Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents, Anti-Cancer Agents in Medicinal Chemistry 2018; 18 (2) . https://dx.doi.org/10.2174/1871520617666170911171152