Anti-proliferative 2,3-dihydro-1,3,4-thiadiazoles targeting VEGFR-2: Design, synthesis, in vitro, and in silico studies

Hazem Elkady; Walid E Elgammal; Hazem A Mahdy; Susi Zara; Simone Carradori; Dalal Z Husein; Aisha A Alsfouk; Ibrahim M Ibrahim; Eslam B Elkaeed; Ahmed M Metwaly; Ibrahim H Eissa

doi:10.1016/j.compbiolchem.2024.108221

Anti-proliferative 2,3-dihydro-1,3,4-thiadiazoles targeting VEGFR-2: Design, synthesis, in vitro, and in silico studies

Comput Biol Chem. 2024 Sep 23:113:108221. doi: 10.1016/j.compbiolchem.2024.108221. Online ahead of print.

Authors

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
² Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt.
³ Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Chieti 66100, Italy.
⁴ Chemistry Department, Faculty of Science, New Valley University, El--Kharja 72511, Egypt.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
⁶ Biophysics Department, Faculty of Science, Cairo University, Giza 12613, Egypt.
⁷ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.. Electronic address: ekaeed@um.edu.sa.
⁸ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: ametwaly@azhar.edu.eg.
⁹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: Ibrahimeissa@azhar.edu.eg.

PMID: 39332241
DOI: 10.1016/j.compbiolchem.2024.108221

Abstract

In this study, we present the design, synthesis, and evaluation of six new thiadiazole derivatives designed as VEGFR-2 inhibitors. The most promising compound, 18b, demonstrated promising inhibitory activity against VEGFR-2, with an IC₅₀ value of 0.165 µg/mL. The in vitro assessments on MCF-7 and HepG2 cell lines revealed the superior anti-proliferative effects of compound 18b, exhibiting IC₅₀ values of 0.06 and 0.17 µM, respectively. Further investigations into the cell cycle distribution of compound 18b on MCF-7 cells exhibited a cell cycle arrest at the S phase (52.96 %) and significantly reducing the percentage of cells in the G0-G1 and G2/M phases. Additionally, compound 18b demonstrated a remarkable pro-apoptotic effect, with 45.29 % total apoptosis, characterized by both early and late apoptosis, and minimal necrosis. These findings were corroborated by RT-PCR analysis, revealing a significant downregulation of the anti-apoptotic gene Bcl2 and upregulation of the pro-apoptotic gene BAX in compound 18b-treated cells compared to control MCF-7 cells. Moreover, in silico studies involving molecular docking, Density Functional Theory (DFT) calculations, Molecular Dynamics (MD) simulations, MM-GBSA, Principle Component Analysis of Trajectories (PCAT), in addition to Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions underscored the molecular interactions, energetics, and pharmacokinetic properties of compound 18b and the other derivatives further supporting its potential. Our integrated approach, combining in vitro experimens with in silico predictions provides valuable insights into the therapeutic potential of compound 18b as a robust VEGFR-2 inhibitor and lays the groundwork for future optimization.

Keywords: Anticancer; Docking; MD simulations; Thiadiazoles; VEGFR-2 inhibitors.