Design of molecular hybrids of phthalimide-triazole agents with potent selective MCF-7/HepG2 cytotoxicity: Synthesis, EGFR inhibitory effect, and metabolic stability

Saleh K Ihmaid; Shaya Yahya Alraqa; Mohamed R Aouad; Ateyatallah Aljuhani; Hossein M Elbadawy; Samir A Salama; Nadjet Rezki; Hany E A Ahmed

doi:10.1016/j.bioorg.2021.104835

Design of molecular hybrids of phthalimide-triazole agents with potent selective MCF-7/HepG2 cytotoxicity: Synthesis, EGFR inhibitory effect, and metabolic stability

Bioorg Chem. 2021 Jun:111:104835. doi: 10.1016/j.bioorg.2021.104835. Epub 2021 Mar 22.

Authors

Saleh K Ihmaid¹, Shaya Yahya Alraqa², Mohamed R Aouad³, Ateyatallah Aljuhani², Hossein M Elbadawy⁴, Samir A Salama⁵, Nadjet Rezki², Hany E A Ahmed⁶

Affiliations

¹ Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia. Electronic address: sihmaid@taibahu.edu.sa.
² Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.
³ Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia. Electronic address: aouadmohamedreda@yahoo.fr.
⁴ Pharmacology and Toxicology Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
⁵ Division of Biochemistry, Department of Pharmacology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia. Electronic address: s.salama@tu.edu.sa.
⁶ Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 11884 Nasr City, Cairo, Egypt.

PMID: 33798850
DOI: 10.1016/j.bioorg.2021.104835

Abstract

This study reports an efficient and convenient click chemistry synthesis of a novel series of phthalimide scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of newly synthesized compounds were well characterized by different spectroscopic tools. In vitro MTT cytotoxicity assay was performed comparing the cytotoxic effects of newly synthesized compounds to staurosporine using three different types: human liver cancer cell line (HepG2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). The initial screening showed excellent to moderate anticancer activity for these newly synthesized compounds with high degree of cell line selectivity with micromolar (µM) half maximal inhibitory concentration (IC₅₀) values against tumor cells. The SAR analysis of these derivatives confirmed the role of molecular fragments including phthalimide, linker, triazole, and terminal tails in correlation to activity. In addition, enzymatic inhibitory assay against wild type EGFR was performed for the most active compounds to get more details about their mechanism of action. In order to further explore their binding affinities, molecular docking simulation was studied against EGFR site. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. One of the most prominent analogs is (6f) with terminal disubstituted ring and amide linker showed selective MCF-7 cytotoxicity profile with IC₅₀ 0.22 µM and 79 nM to EGFR target. Extensive structure activity relationship (SAR) analyses were also carried out. The pharmacokinetic profile of (6f) was studied showing good metabolic stability and long duration behavior. This design offered a potent selective anticancer phthalimide-triazole leads for further optimization in cancer drug discovery.

Keywords: 1,2,3-triazoles; Anticancer activity; Apoptosis study; EGFR kinases; Phthalimide analogues.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Hep G2 Cells
Humans
MCF-7 Cells
Molecular Structure
Phthalimides / chemistry
Phthalimides / metabolism
Phthalimides / pharmacology*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / metabolism
Triazoles / pharmacology*

Substances

Antineoplastic Agents
Phthalimides
Protein Kinase Inhibitors
Triazoles
phthalimide
EGFR protein, human
ErbB Receptors