Discovery of Cyclopentane-Based Phospholipids as Miltefosine Analogs with Superior Potency and Enhanced Selectivity Against <i>Naegleria fowleri</i>

Discovery of Cyclopentane-Based Phospholipids as Miltefosine Analogs with Superior Potency and Enhanced Selectivity Against <i>Naegleria fowleri</i>

<b>Background/Objectives:</b> <i>Naegleria fowleri</i> is a free-living amoeba that invades brain tissues causing fatal primary amoebic meningoencephalitis (PAM). An effective and tolerable therapeutic agent is still lacking. <b>Methods:</b> A series of conformati...

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Main Authors: Ahmed H. E. Hassan, Hương Giang Lê, Tuấn Cường Võ, Minji Kim, Joo Hwan No, Mohamed H. Aboutaleb, Jaehoon Sim, Byoung-Kuk Na, Yong Sup Lee
Format: Article
Language:English
Published: MDPI AG 2025-06-01
Series:Pharmaceuticals
Subjects:
<i>Naegleria fowleri</i>
primary amoebic meningoencephalitis
miltefosine analogs
potential drug
Online Access:https://www.mdpi.com/1424-8247/18/7/984
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Summary:<b>Background/Objectives:</b> <i>Naegleria fowleri</i> is a free-living amoeba that invades brain tissues causing fatal primary amoebic meningoencephalitis (PAM). An effective and tolerable therapeutic agent is still lacking. <b>Methods:</b> A series of conformationally restricted analogs of miltefosine with varied restriction positions, stereochemical configuration and lengths of alkyl chain was investigated to discover more effective and less toxic agents than miltefosine. <b>Results:</b> Among tested compounds, derivatives <b>2a</b>, <b>3b</b> and <b>3d</b> featuring 1,2- or 2,3-positional restriction with <i>trans</i>-configuration and tridecyl or behenyl alkyl chains were discovered as more potent and less cytotoxic agents. Compounds <b>2a</b>, <b>3b</b> and <b>3d</b> elicited 3.49-, 3.58- and 6.03-fold relative potencies to miltefosine and 7.53, 3.90 and 3.49 selectivity indices, respectively. Furthermore, compounds <b>2a</b> and <b>3b</b> showed IC<sub>90</sub> values for <i>N. fowleri</i> lower than CC<sub>50</sub> against glial C6 cells. Compounds <b>2a</b>, <b>3b</b> and <b>3d</b> induced morphological changes and programmed cell death of <i>N. fowleri</i> via the apoptosis-like pathway. The induced death of <i>N. fowleri</i> involved DNA fragmentation along with the loss of mitochondrial membrane potential. <b>Conclusions:</b> The current research presents compounds <b>2a</b> and <b>3b</b> as more potent, selective and effective agents than miltefosine against <i>N. fowleri</i> for further development.
ISSN:1424-8247

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