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

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 EGFR and mutant EGFR for these derivatives revealed that compounds 5, 14c, and 17 have IC value ranging from 85 nM to 71.5 nM against wild EGFR and 37.85-41.19 nM against the mutant type, Lapatinib was used as a reference standard with IC values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further evaluation against double mutant EGFR and showed good IC 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.