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.