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

Lamya H. Al-Wahaibi; Anber F. Mohammed; Mostafa H. Abdelrahman; Laurent Trembleau; Bahaa G.M. Youssif

doi:10.3390/ph16071039

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

Lamya H. Al-Wahaibi^*, Anber F. Mohammed, Mostafa H. Abdelrahman, Laurent Trembleau^*, Bahaa G.M. Youssif^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

A small set of indole-based derivatives, IV and Va–I, was designed and synthesized. Compounds Va–i 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—Va, Ve, Vf, Vg, and Vh—were tested for EGFR inhibitory activity. Compound Va 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 Va, Ve, Vf, Vg, and Vh 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 Va, Ve, Vf, Vg, and Vh 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.

Original language	English
Article number	1039
Number of pages	23
Journal	Pharmaceuticals
Volume	16
Issue number	7
DOIs	https://doi.org/10.3390/ph16071039
Publication status	Published - 22 Jul 2023

Bibliographical note

Funding Information:
The author acknowledge the support by Princess Nourah Bint Abdulrahman University Researchers Supporting Project Number (PNURSP2023R3), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Data Availability Statement

Data are contained within the article and the supplementary materials

Keywords

antiproliferative
apoptosis
docking
indole
kinases

Access to Document

10.3390/ph16071039Licence: CC BY

Al-Wahaibi_etal_P_Design_Synthesis_and_VOR
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Final published version, 3.22 MBLicence: CC BY

Cite this

@article{1fac96ad3a2a4fa797d4708be787900a,

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

abstract = "A small set of indole-based derivatives, IV and Va–I, was designed and synthesized. Compounds Va–i demonstrated promising antiproliferative activity, with GI50 values ranging from 26 nM to 86 nM compared to erlotinib{\textquoteright}s 33 nM. The most potent antiproliferative derivatives—Va, Ve, Vf, Vg, and Vh—were tested for EGFR inhibitory activity. Compound Va 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 Va, Ve, Vf, Vg, and Vh were further tested for BRAFV600E inhibitory activity. The tested compounds inhibited BRAFV600E with IC50 values ranging from 77 nM to 107 nM compared to erlotinib{\textquoteright}s IC50 value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh 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, BRAFV600E, and VEGFR-2.",

keywords = "antiproliferative, apoptosis, docking, indole, kinases",

author = "Al-Wahaibi, {Lamya H.} and Mohammed, {Anber F.} and Abdelrahman, {Mostafa H.} and Laurent Trembleau and Youssif, {Bahaa G.M.}",

note = "Funding Information: The author acknowledge the support by Princess Nourah Bint Abdulrahman University Researchers Supporting Project Number (PNURSP2023R3), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. ",

year = "2023",

month = jul,

day = "22",

doi = "10.3390/ph16071039",

language = "English",

volume = "16",

journal = "Pharmaceuticals",

issn = "1424-8247",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "7",

}

TY - JOUR

T1 - Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents

AU - Al-Wahaibi, Lamya H.

AU - Mohammed, Anber F.

AU - Abdelrahman, Mostafa H.

AU - Trembleau, Laurent

AU - Youssif, Bahaa G.M.

N1 - Funding Information: The author acknowledge the support by Princess Nourah Bint Abdulrahman University Researchers Supporting Project Number (PNURSP2023R3), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

PY - 2023/7/22

Y1 - 2023/7/22

N2 - A small set of indole-based derivatives, IV and Va–I, was designed and synthesized. Compounds Va–i 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—Va, Ve, Vf, Vg, and Vh—were tested for EGFR inhibitory activity. Compound Va 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 Va, Ve, Vf, Vg, and Vh were further tested for BRAFV600E inhibitory activity. The tested compounds inhibited BRAFV600E with IC50 values ranging from 77 nM to 107 nM compared to erlotinib’s IC50 value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh 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, BRAFV600E, and VEGFR-2.

AB - A small set of indole-based derivatives, IV and Va–I, was designed and synthesized. Compounds Va–i 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—Va, Ve, Vf, Vg, and Vh—were tested for EGFR inhibitory activity. Compound Va 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 Va, Ve, Vf, Vg, and Vh were further tested for BRAFV600E inhibitory activity. The tested compounds inhibited BRAFV600E with IC50 values ranging from 77 nM to 107 nM compared to erlotinib’s IC50 value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh 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, BRAFV600E, and VEGFR-2.

KW - antiproliferative

KW - apoptosis

KW - docking

KW - indole

KW - kinases

UR - http://www.scopus.com/inward/record.url?scp=85166324256&partnerID=8YFLogxK

U2 - 10.3390/ph16071039

DO - 10.3390/ph16071039

M3 - Article

AN - SCOPUS:85166324256

SN - 1424-8247

VL - 16

JO - Pharmaceuticals

JF - Pharmaceuticals

IS - 7

M1 - 1039

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

Access to Document

Other files and links

Fingerprint

Cite this