Metronidazole aryloxy, carboxy and azole derivatives: Synthesis, anti-tumor activity, QSAR, molecular docking and dynamics studies

Ehsan Faghih-Mirzaei; Salehe Sabouri; Leila Zeidabadinejad; Salman AbdolahRamazani; Mehdi Abaszadeh; Arash Khodadadi; Mohadeseh Shamsadinipour; Mandana Jafari; Somayeh Pirhadi

doi:10.1016/j.bmc.2018.12.003

Metronidazole aryloxy, carboxy and azole derivatives: Synthesis, anti-tumor activity, QSAR, molecular docking and dynamics studies

Bioorg Med Chem. 2019 Jan 15;27(2):305-314. doi: 10.1016/j.bmc.2018.12.003. Epub 2018 Dec 4.

Authors

Ehsan Faghih-Mirzaei¹, Salehe Sabouri², Leila Zeidabadinejad³, Salman AbdolahRamazani⁴, Mehdi Abaszadeh⁵, Arash Khodadadi⁶, Mohadeseh Shamsadinipour⁶, Mandana Jafari⁷, Somayeh Pirhadi⁸

Affiliations

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
² Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Herbal and Traditional Medicine Research Center, Kerman University of Medical Sciences, Kerman, Iran.
³ Department of Chemistry, Shahid Bahonar University of Kerman, Kerman, Iran.
⁴ Medicinal Chemistry Department, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
⁵ Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 76175493, Iran. Electronic address: abaszadeh@kmu.ac.ir.
⁶ Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 76175493, Iran.
⁷ Herbal and Traditional Medicine Research Center, Kerman University of Medical Sciences, Kerman, Iran.
⁸ Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: s_pirhadi@sums.ac.ir.

PMID: 30554970
DOI: 10.1016/j.bmc.2018.12.003

Abstract

A series of novel metronidazole aryloxy, carboxy and azole derivatives has been synthesized and their cytotoxic activities on three cancer cell lines were evaluated by MTT assay. Compounds 4m, 4l and 4d showed the most potent cytotoxic activity (IC₅₀s less than 100 µg/mL). Apoptosis was also detected for these compounds by flow cytometry. Docking studies were performed in order to propose the probable target protein. In the next step, molecular dynamics simulation was carried out on the proposed target protein, focal adhesion kinase (FAK, PDB code: 2ETM), bound to compound 4m. As, 4m showed a potent cytotoxic activity and an acceptable apoptotic effect, it can be a potential anticancer candidate that may work through inhibition of FAK.

Keywords: Apoptosis; Cancer; Docking; MTT; Metronidazole; Molecular dynamics simulation; QSAR; Synthesis.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Focal Adhesion Kinase 1 / antagonists & inhibitors
Focal Adhesion Kinase 1 / chemistry
Focal Adhesion Kinase 1 / metabolism
Humans
Hydrogen Bonding
Metronidazole / analogs & derivatives*
Metronidazole / chemical synthesis
Metronidazole / metabolism
Metronidazole / pharmacology*
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Quantitative Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Metronidazole
Focal Adhesion Kinase 1
PTK2 protein, human