Design and synthesis new indole-based aromatase/iNOS inhibitors with apoptotic antiproliferative activity

Lamya H. Al-Wahaibi; Hesham A. Abou-Zied; Mostafa H. Abdelrahman; Martha M. Morcoss; Laurent Trembleau; Bahaa G.M. Youssif; Stefan Bräse

doi:10.3389/fchem.2024.1432920

Design and synthesis new indole-based aromatase/iNOS inhibitors with apoptotic antiproliferative activity

Lamya H. Al-Wahaibi, Hesham A. Abou-Zied, Mostafa H. Abdelrahman, Martha M. Morcoss, Laurent Trembleau^* (Corresponding Author), Bahaa G.M. Youssif^* (Corresponding Author), Stefan Bräse^* (Corresponding Author)

^*Corresponding author for this work

Chemistry

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

1 Citation (Scopus)

Abstract

The present study details the design, synthesis, and bio-evaluation of indoles 3–16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3–16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7, 12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids’ 12- and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8–16, highlighting their potential as therapeutic agents with reduced toxicity.

Original language	English
Article number	1432920
Number of pages	19
Journal	Frontiers in Chemistry
Volume	12
Early online date	6 Sept 2024
DOIs	https://doi.org/10.3389/fchem.2024.1432920
Publication status	Published - 6 Sept 2024

Data Availability Statement

Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2024.1432920/full#supplementary-material

Keywords

aromatase
indole
inhibitors
nitric oxide
pyrazine
synthase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3389/fchem.2024.1432920Licence: CC BY

Al-Wahaibi_etal_FC_Design_And_Synthesis_VoR
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. https://creativecommons.org/licenses/by/4.0/
Final published version, 3.5 MBLicence: CC BY

Cite this

@article{96d8ebbd97f4425c857efb53c07bd0e5,

title = "Design and synthesis new indole-based aromatase/iNOS inhibitors with apoptotic antiproliferative activity",

abstract = "The present study details the design, synthesis, and bio-evaluation of indoles 3–16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3–16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7, 12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids{\textquoteright} 12- and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8–16, highlighting their potential as therapeutic agents with reduced toxicity.",

keywords = "aromatase, indole, inhibitors, nitric oxide, pyrazine, synthase",

author = "Al-Wahaibi, {Lamya H.} and Abou-Zied, {Hesham A.} and Abdelrahman, {Mostafa H.} and Morcoss, {Martha M.} and Laurent Trembleau and Youssif, {Bahaa G.M.} and Stefan Br{\"a}se",

year = "2024",

month = sep,

day = "6",

doi = "10.3389/fchem.2024.1432920",

language = "English",

volume = "12",

journal = "Frontiers in Chemistry",

issn = "2296-2646",

publisher = "Frontiers Media SA",

}

TY - JOUR

T1 - Design and synthesis new indole-based aromatase/iNOS inhibitors with apoptotic antiproliferative activity

AU - Al-Wahaibi, Lamya H.

AU - Abou-Zied, Hesham A.

AU - Abdelrahman, Mostafa H.

AU - Morcoss, Martha M.

AU - Trembleau, Laurent

AU - Youssif, Bahaa G.M.

AU - Bräse, Stefan

PY - 2024/9/6

Y1 - 2024/9/6

N2 - The present study details the design, synthesis, and bio-evaluation of indoles 3–16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3–16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7, 12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids’ 12- and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8–16, highlighting their potential as therapeutic agents with reduced toxicity.

AB - The present study details the design, synthesis, and bio-evaluation of indoles 3–16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3–16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7, 12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids’ 12- and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8–16, highlighting their potential as therapeutic agents with reduced toxicity.

KW - aromatase

KW - indole

KW - inhibitors

KW - nitric oxide

KW - pyrazine

KW - synthase

UR - http://www.scopus.com/inward/record.url?scp=85204744451&partnerID=8YFLogxK

U2 - 10.3389/fchem.2024.1432920

DO - 10.3389/fchem.2024.1432920

M3 - Article

AN - SCOPUS:85204744451

SN - 2296-2646

VL - 12

JO - Frontiers in Chemistry

JF - Frontiers in Chemistry

M1 - 1432920

ER -

Design and synthesis new indole-based aromatase/iNOS inhibitors with apoptotic antiproliferative activity

Abstract

Data Availability Statement

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this