Exploration of thiazolidine‐2,4‐diones as tyrosine kinase inhibitors: Design, synthesis, ADMET, docking, and antiproliferative evaluations

• Published in: Archiv der Pharmazie (Weinheim) 2023-03, Vol.356 (3), p.e2200465-n/a
• Main Authors: Aziz, Nada A. A. M., George, Riham F., El‐Adl, Khaled, Mahmoud, Walaa R.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; antiproliferative agents; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; dual inhibition of VEGFR‐2/EGFRT790M; ErbB Receptors - metabolism; Erlotinib Hydrochloride - pharmacology; Humans; Lung Neoplasms; molecular docking; Molecular Docking Simulation; Molecular Structure; Mutation; Protein Kinase Inhibitors - chemistry; Sorafenib - pharmacology; Structure-Activity Relationship; Thiazolidines - pharmacology; thiazolidine‐2,4‐diones; Tyrosine Kinase Inhibitors; Vascular Endothelial Growth Factor Receptor-2
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202200465

As dual EGFR and VEGFR‐2 inhibitors, 22 innovative thiazolidine‐2,4‐diones were modeled, constructed, and measured for their anticancer performance versus four human neoplasms HCT‐116, MCF‐7, A549, and HepG2. Molecular docking and MD simulation were performed to inspect the binding technique of the proffered congeners with the EGFR and VEGFR‐2 receptors. Evidence realized thanks to the docking inquests was vastly consistent together with that detected through the biological screening. Structures 14a and 14g emerged as the most active compounds toward HCT116 (IC50 = 6.01 and 7.44 µM), MCF‐7 (IC50 = 5.77 and 7.23 µM), A549 (IC50 = 5.35 and 5.47 µM) and HepG2 (IC50 = 3.55 and 3.85 µM) tumefaction cells. Compounds 14a and 14g exhibited higher events than sorafenib (IC50 = 5.05, 5.58, 4.04, and 4.00 µM) against HepG2 instead subordinate incidents concerning A549, MCF‐7, and HCT116, parallelly. Nevertheless, these compounds signified weightier performance than erlotinib (IC50 = 13.91, 8.20, 5.49, 7.73, and µM), with respect to the four cell lines. Compounds having the best activity against the four cell lines, 12a–f, 13a–d, and 14a–g were chosen to appraise their in vitro VEGFR‐2 and EGFRT790M inhibiting activities. The best results were for compounds 14a and 14g compared to sorafenib and erlotinib, respectively, with IC50 values of 0.74 and 0.78 µM and 0.12 and 0.14 µM, respectively. Moreover, 13d, 14a, and 14g showed an adequate in silico calculated ADMET profile. The current investigation presents novel candidates for future optimization to construct mightier and eclectic binary VEGFR‐2/EGFRT790M restrainers with higher antitumor effects. Twenty‐two new thiazolidine‐2,4‐diones were modeled, constructed, and measured for their activity against four human cancer cell lines: HCT‐116, MCF‐7, A549, and HepG2. Molecular docking and MD simulation were performed to study the binding modes of the new congeners with the EGFR and VEGFR‐2 receptors. Novel candidates were identified to construct better and binary VEGFR‐2/EGFRT790M inhibitors with higher antitumor effects.