1. Academic Validation
  2. New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies

New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies

  • ACS Omega. 2024 Mar 6;9(11):13359-13372. doi: 10.1021/acsomega.3c10345.
Ulviye Acar Çevik 1 Betül Kaya 2 Ismail Celik 3 Mithun Rudrapal 4 Gourav Rakshit 5 Arzu Karayel 6 Serkan Levent 1 Derya Osmaniye 1 Begüm Nurpelin Sağlık Özkan 1 Merve Baysal 7 Özlem Atlı Ekliog Lu 7 Yusuf Özkay 1 Zafer Asım Kaplancıklı 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eski̧ehir 26470, Turkey.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Zonguldak Bülent Ecevit University, Zonguldak 67100, Turkey.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey.
  • 4 Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research (Deemed to Be University), Guntur 522213, India.
  • 5 Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Ranchi 835215, India.
  • 6 Department of Physics, Faculty of Arts and Science, Hitit University, Çorum 19030, Turkey.
  • 7 Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Anadolu University, Eski̧ehir 26470, Turkey.
Abstract

In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA Topoisomerase I, aiming to develop novel Anticancer agents. The synthesized final compounds 4a-h were characterized using 1H NMR, 13C NMR, and HRMS. Among them, compounds 4b and 4h emerged as the most potent agents against the A549 cell line, exhibiting an IC50 value of 7.34 ± 0.21 μM and 4.56 ± 0.18 μM, respectively. These results were compared to standard drugs, doxorubicin (IC50 = 12.420 ± 0.5 μM) and Hoechst 33342 (IC50 = 0.422 ± 0.02 μM). Notably, all tested compounds displayed higher cytotoxicity toward A549 cells than C6 cells. Compounds 4b and 4h demonstrated significant inhibitory activity against Topoisomerase I, highlighting their potential as lead compounds in Anticancer therapy. Subsequent in silico molecular docking studies were conducted to elucidate the potential binding interactions of compounds 4b and 4h with the target enzyme Topoisomerase I. Molecular dynamics studies also assessed and validated the binding affinity and stability. These studies confirmed the promising binding affinity of these compounds, reinforcing their status as lead candidates. According to DFT, compound 4b having the lower energy gap value (ΔE = 3.598 eV) is more chemically reactive than the Others, which is consistent with significant inhibitory activity against Topoisomerase I. Furthermore, in silico ADME profiles for compounds 4b and 4h were evaluated using SwissADME, providing insights into their pharmacokinetic properties.

Figures
Products