Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents

• Main Authors: Lamya H. Al-Wahaibi (Author), Anber F. Mohammed (Author), Mostafa H. Abdelrahman (Author), Laurent Trembleau (Author), Bahaa G. M. Youssif (Author)
• Format: Book
• Published: MDPI AG, 2023-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

A small set of indole-based derivatives, <b>IV</b> and <b>Va</b>-<b>I</b>, was designed and synthesized. Compounds <b>Va</b>-<b>i</b> demonstrated promising antiproliferative activity, with GI₅₀ values ranging from 26 nM to 86 nM compared to erlotinib's 33 nM. The most potent antiproliferative derivatives-<b>Va</b>, <b>Ve</b>, <b>Vf</b>, <b>Vg</b>, and <b>Vh</b>-were tested for EGFR inhibitory activity. Compound <b>Va</b> demonstrated the highest inhibitory activity against EGFR with an IC₅₀ value of 71 ± 06 nM, which is higher than the reference erlotinib (IC₅₀ = 80 ± 05 nM). Compounds <b>Va</b>, <b>Ve</b>, <b>Vf</b>, <b>Vg</b>, and <b>Vh</b> were further tested for BRAF^V600E inhibitory activity. The tested compounds inhibited BRAF^V600E with IC₅₀ values ranging from 77 nM to 107 nM compared to erlotinib's IC₅₀ value of 60 nM. The inhibitory activity of compounds <b>Va</b>, <b>Ve</b>, <b>Vf</b>, <b>Vg</b>, and <b>Vh</b> against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAF^V600E, and VEGFR-2.

Item Description

10.3390/ph16071039
1424-8247