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

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 16; no. 7; p. 1039
• Main Authors: Al-Wahaibi, Lamya H, Mohammed, Anber F, Abdelrahman, Mostafa H, Trembleau, Laurent, Youssif, Bahaa G M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-07-2023; MDPI
• Subjects: Antimitotic agents; Antineoplastic agents; antiproliferative; apoptosis; Breast cancer; Cancer therapies; Chemical properties; Colorectal cancer; docking; FDA approval; Indole; Kinases; Medical prognosis; Melanoma; Proteins; Structure; Thyroid gland; Vascular endothelial growth factor; Saudi Arabia; docking; apoptosis; indole; kinases; antiproliferative
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph16071039

A small set of indole-based derivatives,
and
-
, was designed and synthesized. Compounds
-
demonstrated promising antiproliferative activity, with GI
values ranging from 26 nM to 86 nM compared to erlotinib's 33 nM. The most potent antiproliferative derivatives-
,
,
,
, and
-were tested for EGFR inhibitory activity. Compound
demonstrated the highest inhibitory activity against EGFR with an IC
value of 71 ± 06 nM, which is higher than the reference erlotinib (IC
= 80 ± 05 nM). Compounds
,
,
,
, and
were further tested for BRAF
inhibitory activity. The tested compounds inhibited BRAF
with IC
values ranging from 77 nM to 107 nM compared to erlotinib's IC
value of 60 nM. The inhibitory activity of compounds
,
,
,
, and
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
, and VEGFR-2.