Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments

Abstract

Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the telomerase target was investigated. Notably, <b>6f</b> achieved superior telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, <b>8a</b> and <b>8b</b> showed comparable promising telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. <b>6f</b>, <b>8a</b>, and <b>8b</b> were tested against five cancer cell lines related to the lung and liver subtypes. Moreover, <b>6f</b> was examined on both cell cycle progression and apoptosis induction in HuH7 cancer cells. Furthermore, the in vivo antitumor activity of <b>6f</b> was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, <b>6f</b>, <b>8a</b>, and <b>8b</b> could be considered potential new telomerase inhibitors to be subjected to further investigation and/or optimization.