Development of adamantane scaffold containing 1,3,4-thiadiazole derivatives: Design, synthesis, anti-proliferative activity and molecular docking study targeting EGFR

• Published in: Bioorganic chemistry 2021-05, Vol.110, p.104794, Article 104794
• Main Authors: Wassel, Mohammed M.S., Ammar, Yousry A., Elhag Ali, Gameel A.M., Belal, Amany, Mehany, Ahmed B.M., Ragab, Ahmed
• Format: Article
• Language: English
• Subjects: 1,3,4-Thiadiazole derivatives; Adamantane; Anti-proliferative activity; Apoptosis and molecular docking; EGFR
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104794

Plausible targets and the obtained results for the most promising three adamantane derivatives 5, 14c and 17 and Erlotinib. [Display omitted] •New 1,3,4-Thiadiazolo-adamantane derivatives containing were synthetized.•In vitro anti-proliferative screening activity and SAR study were discussed.•Mitochondrial apoptosis pathway BAX and Bcl-2 proteins were evaluated.•Wide, mutant EGFR inhibitions, apoptosis and cell cycle analysis were determined.•Molecular docking and some physicochemical properties were performed. A new series of 1,3,4-thiadiazolo-adamantane derivatives were synthesized through molecular hybridization approach, then used as starting material to synthesize chloro and cyano acetamide-thiadiazole derivatives 2, 3. The newly designed compounds 1–3 were treated with different reagents to design 5-adamantyl thiadiazole derivatives 4–17 and evaluate their in vitro anti-proliferative activity against three cancer cell lines (MCF-7, HepG-2 and A549). Doxorubicin was used as a positive control. The most promising compounds 5, 6, 10a, 10b, 14b, 14c, and 17 showed up-regulation for BAX and down-regulation of Bcl-2, these findings proved their role as hopeful apoptotic inducers. In addition, the inhibitory activity against both wild EGFRWT and mutant EGFRL858R-TK for these derivatives revealed that compounds 5, 14c, and 17 have IC50 value ranging from 85 nM to 71.5 nM against wild EGFRWT and 37.85–41.19 nM against the mutant type, Lapatinib was used as a reference standard with IC50 values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further evaluation against double mutant EGFR L858R/T790M and showed good IC50 values between (0.27–0.78 nM) compared to Lapatinib (0.18 nM) and Erlotinib (0.21 nM). Among them, thiazolo-thiadiazole adamantane derivative 17 exhibited the strongest inhibitory activity to the EGFR. Molecular docking studies were performed inside the active site of EGFR (1M17), and binding energy scores ranged between (−19.19 to –22.07 Kcal/mol) compared to Erlotinib (−19.10 Kcal/mol). Furthermore, oral bioavailability beside some pharmacokinetics properties of these derivatives were also investigated in this research work.