Design and synthesis of novel benzoazoninone derivatives as potential CBSIs and apoptotic inducers: In Vitro, in Vivo, molecular docking, molecular dynamics, and SAR studies

Mohamed M Hammouda; Ayman Abo Elmaaty; Mohamed S Nafie; Marwa Abdel-Motaal; Noha S Mohamed; Mohamed A Tantawy; Amany Belal; Radwan Alnajjar; Wagdy M Eldehna; Ahmed A Al-Karmalawy

doi:10.1016/j.bioorg.2022.105995

Design and synthesis of novel benzoazoninone derivatives as potential CBSIs and apoptotic inducers: In Vitro, in Vivo, molecular docking, molecular dynamics, and SAR studies

Bioorg Chem. 2022 Oct:127:105995. doi: 10.1016/j.bioorg.2022.105995. Epub 2022 Jun 30.

Authors

Affiliations

¹ Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt. Electronic address: elmhammouda@mans.edu.eg.
² Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt. Electronic address: ayman.mohamed@pharm.psu.edu.eg.
³ Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt. Electronic address: mohamed_nafie@science.suez.edu.eg.
⁴ Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt; Department of Chemistry, College of Science, Qassim University, Buraydah 51452, Saudi Arabia. Electronic address: dr_marwachem@mans.edu.eg.
⁵ Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
⁶ Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza 12622, Egypt; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza 12622, Egypt. Electronic address: mohamed_tantawy@daad-alumni.de.
⁷ Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁸ Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya; Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: radwan.alnajjar@uob.edu.ly.
⁹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
¹⁰ Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt. Electronic address: akarmalawy@horus.edu.eg.

PMID: 35792315
DOI: 10.1016/j.bioorg.2022.105995

Abstract

Apparently, tubulin inhibitors binding to the colchicine-binding site (CBS) currently have outstanding attention for cancer treatment. So, a series of benzo[b]azonin-2-one derivatives having the same pharmacophoric features as colchicine binding site inhibitors (CBSIs) were synthesized targeting the CBS of β-tubulin. The antiproliferative activities of the newly synthesized compounds were assessed against five different cancer cell lines; HepG-2, MCF-7, MDA-MB-231, HCT-116, and Caco-2. Compounds 7a and 7d displayed promising inhibitory activities against all tested cell lines. They were further estimated towards β-tubulin at CBS along with colchicine (Col) as a reference drug. It was shown that the assessed candidates (7a and 7d) and Col exhibited CBSI activities of 5492, 3771, and 486c.p.m./mg protein, respectively, at a concentration of 10 µM. Furthermore, compound 7d was picked out to assess its effects on apoptosis and cell-cycle profile using Annexin V-FITC and PI staining assay. In addition, the apoptotic activity of 7d was investigated using gene expression analysis of apoptosis-related genes of P53, Bax, Caspases 3 and 9, and Bcl-2 in both treated and untreated cells. Moreover, compound 7d was further assessed through in vivo studies using solid Ehrlich carcinoma (SEC)-bearing mice. Furthermore, both molecular docking and molecular dynamics simulations (for 150 ns) were performed to investigate their mechanism of action as potential CBSIs and give more insights into the behavior of the examined candidates within the β-tubulin subunit of the CBS. On the other hand, in silico ADMET studies were carried out to assess the pharmacokinetic features, drug/lead likeness, and toxicity parameters of the newly synthesized derivatives. Finally, to anticipate the possible changes in the antimitotic activities upon future structural modifications of the investigated compounds, a structure-activity relationship study (SAR) was accomplished.

Keywords: Apoptosis genes; Benzoazoninone derivatives; CBSIs; SAR.

MeSH terms

Animals
Antineoplastic Agents* / chemistry
Binding Sites
Caco-2 Cells
Cell Proliferation
Colchicine / pharmacology
Drug Screening Assays, Antitumor
Humans
Mice
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Structure-Activity Relationship
Tubulin* / metabolism

Substances

Antineoplastic Agents
Tubulin
Colchicine