New [1,2,4]triazolo[4,3-c]quinazolines as intercalative Topo II inhibitors: Design, synthesis, biological evaluation, and in silico studies

Ahmed A Gaber; Mohamed Sobhy; Abdallah Turky; Wagdy M Eldehna; Samiha A El-Sebaey; Souad A El-Metwally; Abeer M El-Naggar; Ibrahim M Ibrahim; Eslam B Elkaeed; Ahmed M Metwaly; Ibrahim H Eissa

doi:10.1371/journal.pone.0274081

New [1,2,4]triazolo[4,3-c]quinazolines as intercalative Topo II inhibitors: Design, synthesis, biological evaluation, and in silico studies

PLoS One. 2023 Jan 30;18(1):e0274081. doi: 10.1371/journal.pone.0274081. eCollection 2023.

Authors

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
⁴ Department of Basic Science, Higher Technological institute, 10th of Ramadan City, Egypt.
⁵ Department of Chemistry, Faculty of Science, Ain Shams University, Abassia, Cairo, Egypt.
⁶ Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
⁷ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah, Riyadh, Saudi Arabia.
⁸ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁹ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
¹⁰ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Abstract

Fifteen quinazoline derivatives were designed and synthesized as DNA intercalators. The cytotoxicity of the designed members was assessed against HCT-116 and HepG2 cancer cell lines. In addition, the topoisomerase II (Topo II) inhibitory effect was assessed. Compound 16 was the most cytotoxic and Topo II inhibitor with low cytotoxicity against Vero cells. Compounds 16, 17, and 18 showed significant DNA binding affinities. Compound 16 showed Topo II catalytic inhibitory effect at a concentration of 10 μM. Further mechanistic investigations revealed the capability of compound 16 to induce apoptosis in HCT-116 cells and arrest the growth at the S and G2/M phases. Also, compound 16 showed a significant increase in the level of BAX (2.18-fold) and a marked decrease in the level of Bcl-2 (1.9-fold) compared to the control cells. In silico studies revealed the ability of the synthesized members to bind to the DNA-Topo II complex.

Copyright: © 2023 Gaber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Chlorocebus aethiops
DNA / metabolism
DNA Topoisomerases, Type II / metabolism
Drug Design
Drug Screening Assays, Antitumor
Molecular Structure
Quinazolines / pharmacology
Structure-Activity Relationship
Topoisomerase II Inhibitors* / pharmacology
Vero Cells

Substances

Topoisomerase II Inhibitors
Quinazolines
Antineoplastic Agents
DNA
DNA Topoisomerases, Type II

Grants and funding

This research is funded by AlMaarefa University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.