Synthesis and In Silico Evaluation of Novel Benzofuran Aldehyde Derivatives as Carbonic Anhydrase II Inhibitors in Breast Cancer: Combining ADMET, Molecular Docking, Dynamics Simulation, DFT, and Topology Analysis

Najri B. A., Saidi K. M., Guendouzi A., Khelili S., KIVRAK A.

Journal of Molecular Structure, cilt.1340, 2025 (SCI-Expanded) identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1340
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.molstruc.2025.142482
  • Dergi Adı: Journal of Molecular Structure
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, INSPEC
  • Anahtar Kelimeler: Benzofuran aldehyde derivatives, breast cancer therapy, carbonic anhydrase inhibitors, in silico
  • Eskişehir Osmangazi Üniversitesi Adresli: Evet

Özet

This study presents the synthesis and in silico evaluation of novel benzofuran aldehyde derivatives (3a-3o) as potential carbonic anhydrase II (CA-II) inhibitors for breast cancer therapy. The synthesis was accomplished using a three-step process that included Suzuki-Miyaura coupling reaction, combining 3-iodo-2-alkyl/aryl-benzofuran with various boronic acids to produce high-yield aldehyde derivatives. The resulting compounds (3a-3o) underwent structural and purity confirmation through characterization techniques, including 1H NMR, 13C NMR, and FTIR. All the compounds met Lipinski's Rule of Five criteria, indicating their potential as viable drug candidates. The ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of the synthesized compounds were thoroughly evaluated, revealing promising profiles that suggest good bioavailability and safety. Among the synthesized derivatives, compound 3j emerged as a standout, demonstrating a high binding affinity of -9.56 kcal/mol in molecular docking studies, alongside forming a stable hydrogen bond with SER197 at a distance of 3.22 ⁰A. In contrast, the reference drug tamoxifen (TAM) exhibited a lower binding energy of -8.07 kcal/mol. Molecular dynamics simulations verified the stability of the tested compounds, assessing root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg). Over the course of a 100 ns simulation, compound 3j demonstrated superior stability compared to the others. Density Functional Theory (DFT) calculations revealed the energy gap (ΔE) varied from 6.885 eV (3h) to 7.216 eV (3a), with compound 3j exhibiting favorable properties for stability and reactivity. Topology analysis of compound (3a-3o) further illuminated its electronic structure, utilizing the Electron Localization Function (ELF) and Localized Orbital Locator (LOL) to visualize electron density and bonding characteristics. This analysis revealed significant electron localization within covalent bonds, indicating strong stability and reactivity potential, which may enhance its therapeutic efficacy. These findings underscore the potential of benzofuran aldehyde derivatives, particularly 3j, as targeted therapies for breast cancer, warranting further preclinical and clinical investigations.