Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations.

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 is a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[ b ]thiophene ( 8a-f ) and tetrahydro-1-benzothiophene ( 9a-f ) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the telomerase inhibitory activity of candidates. Notably, 8e and 9e exhibited the best inhibition profiles. Moreover, 8e showed strong antitumor effects against both MCF-7 and A549 cancer cell lines. The effects of 8e on the cell cycle and apoptosis were measured. Besides, 8e was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different telomerase inhibition potentials upon variable structural modifications.