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

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“…The experiment design, detailed methodology of tumor inoculation, treatments, and blood measurements were performed according to a reported procedure 49,50 as described in the ESI †. The experimental protocol is summarized in Fig.…”

Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses

“…By simulating molecular behavior, it provides insights into stability, solubility, target affinity, and interactions. Trajectory analysis identifies key conformations and interactions, guiding the selection of promising candidates for further investigation ( Al-Karmalawy et al, 2023 ; Buskes et al, 2023 ).…”

“…By simulating molecular behavior, it provides insights into stability, solubility, target affinity, and interactions. Trajectory analysis identifies key conformations and interactions, guiding the selection of promising candidates for further investigation (Al-Karmalawy et al, 2023;Buskes et al, 2023). The present study analyzed metrics including energy, pressure, temperature, drift extracted, RMSD, RMSF, SASA, RoG, and Hbonds from 100ns simulations, to validate the stability and convergence of different ligand-protein complexes (Figure 10; Figure 13).…”

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