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ORIGINAL RESEARCH article

Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 12 - 2024 | doi: 10.3389/fchem.2024.1432920
This article is part of the Research Topic Five-membered Ring Heterocyclic Compounds as Anticancer Drug Candidates View all articles

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

Provisionally accepted
Lamya H. Al-Wahaibi Lamya H. Al-Wahaibi 1Hesham A. Abou-Zied Hesham A. Abou-Zied 2Mostafa H. Abdelrahman Mostafa H. Abdelrahman 3Laurent Trembleau Laurent Trembleau 4Bahaa G. Youssif Bahaa G. Youssif 5Stefan Bräse Stefan Bräse 6*
  • 1 Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
  • 2 Deraya University, New Minia, Egypt
  • 3 Faculty of Pharmacy, Al Azhar University, Assiut, Egypt
  • 4 University of Aberdeen, Aberdeen, Scotland, United Kingdom
  • 5 Assiut University, Assiut, Egypt
  • 6 Karlsruhe Institute of Technology (KIT), Karlsruhe, Baden-Württemberg, Germany

The final, formatted version of the article will be published soon.

    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.

    Keywords: indole, Pyrazine, Aromatase, Nitric Oxide, Synthase, inhibitors

    Received: 14 May 2024; Accepted: 26 Aug 2024.

    Copyright: © 2024 Al-Wahaibi, Abou-Zied, Abdelrahman, Trembleau, Youssif and Bräse. 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) or licensor 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.

    * Correspondence: Stefan Bräse, Karlsruhe Institute of Technology (KIT), Karlsruhe, 76344, Baden-Württemberg, Germany

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