Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents
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 GI<sub>50</sub> values ranging from 26...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-07-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/7/1039 |
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| author | Lamya H. Al-Wahaibi Anber F. Mohammed Mostafa H. Abdelrahman Laurent Trembleau Bahaa G. M. Youssif |
| author_facet | Lamya H. Al-Wahaibi Anber F. Mohammed Mostafa H. Abdelrahman Laurent Trembleau Bahaa G. M. Youssif |
| author_sort | Lamya H. Al-Wahaibi |
| collection | DOAJ |
| description | 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 GI<sub>50</sub> 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 IC<sub>50</sub> value of 71 ± 06 nM, which is higher than the reference erlotinib (IC<sub>50</sub> = 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<sup>V600E</sup> inhibitory activity. The tested compounds inhibited BRAF<sup>V600E</sup> with IC<sub>50</sub> values ranging from 77 nM to 107 nM compared to erlotinib’s IC<sub>50</sub> 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<sup>V600E</sup>, and VEGFR-2. |
| first_indexed | 2024-03-11T00:44:57Z |
| format | Article |
| id | doaj.art-8062d6f4429b4bc593f55c9df3f2069d |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T00:44:57Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-8062d6f4429b4bc593f55c9df3f2069d2023-11-18T20:53:31ZengMDPI AGPharmaceuticals1424-82472023-07-01167103910.3390/ph16071039Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative AgentsLamya H. Al-Wahaibi0Anber F. Mohammed1Mostafa H. Abdelrahman2Laurent Trembleau3Bahaa G. M. Youssif4Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11564, Saudi ArabiaPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, EgyptPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut 71234, EgyptSchool of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB24 3UE, UKPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, EgyptA 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 GI<sub>50</sub> 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 IC<sub>50</sub> value of 71 ± 06 nM, which is higher than the reference erlotinib (IC<sub>50</sub> = 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<sup>V600E</sup> inhibitory activity. The tested compounds inhibited BRAF<sup>V600E</sup> with IC<sub>50</sub> values ranging from 77 nM to 107 nM compared to erlotinib’s IC<sub>50</sub> 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<sup>V600E</sup>, and VEGFR-2.https://www.mdpi.com/1424-8247/16/7/1039indoleantiproliferativeapoptosiskinasesdocking |
| spellingShingle | Lamya H. Al-Wahaibi Anber F. Mohammed Mostafa H. Abdelrahman Laurent Trembleau Bahaa G. M. Youssif Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents Pharmaceuticals indole antiproliferative apoptosis kinases docking |
| title | Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents |
| title_full | Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents |
| title_fullStr | Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents |
| title_full_unstemmed | Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents |
| title_short | Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents |
| title_sort | design synthesis and biological evaluation of indole 2 carboxamides as potential multi target antiproliferative agents |
| topic | indole antiproliferative apoptosis kinases docking |
| url | https://www.mdpi.com/1424-8247/16/7/1039 |
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