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

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

JOURNAL=Frontiers in Chemistry

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2024.1432920

DOI=10.3389/fchem.2024.1432920

ISSN=2296-2646

ABSTRACT=<p>The present study details the design, synthesis, and bio-evaluation of indoles <bold>3–16</bold> as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS)with antiproliferative activity. The study evaluates the antiproliferative efficacy of <bold>3–16</bold> against various cancer cell lines, highlighting hybrids <bold>12</bold> and <bold>16</bold> for their exceptional activity with GI<sub>50</sub> values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids <bold>5, 7, 12</bold>, and <bold>16</bold>, on both aromatase and iNOS were evaluated. Compounds <bold>12</bold> and <bold>16</bold> 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’ <bold>12-</bold> and <bold>16</bold>-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives <bold>8–16</bold>, highlighting their potential as therapeutic agents with reduced toxicity.</p>