# Discovery of Cyclopentane-Based Phospholipids as Miltefosine Analogs with Superior Potency and Enhanced Selectivity Against Naegleria fowleri

## TL;DR

Researchers developed new cyclopentane-based phospholipids that are more effective and less toxic than miltefosine in fighting the deadly brain amoeba Naegleria fowleri.

## Contribution

The study introduces cyclopentane-based phospholipid analogs of miltefosine with improved potency and selectivity against Naegleria fowleri.

## Key findings

- Compounds 2a, 3b, and 3d showed 3.49- to 6.03-fold higher potency than miltefosine against Naegleria fowleri.
- These compounds induced programmed cell death in N. fowleri via apoptosis-like pathways and DNA fragmentation.
- Compounds 2a and 3b exhibited IC90 values lower than CC50 against glial cells, indicating high selectivity.

## Abstract

Background/Objectives: Naegleria fowleri is a free-living amoeba that invades brain tissues causing fatal primary amoebic meningoencephalitis (PAM). An effective and tolerable therapeutic agent is still lacking. Methods: 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. Results: Among tested compounds, derivatives 2a, 3b and 3d featuring 1,2- or 2,3-positional restriction with trans-configuration and tridecyl or behenyl alkyl chains were discovered as more potent and less cytotoxic agents. Compounds 2a, 3b and 3d 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 2a and 3b showed IC90 values for N. fowleri lower than CC50 against glial C6 cells. Compounds 2a, 3b and 3d induced morphological changes and programmed cell death of N. fowleri via the apoptosis-like pathway. The induced death of N. fowleri involved DNA fragmentation along with the loss of mitochondrial membrane potential. Conclusions: The current research presents compounds 2a and 3b as more potent, selective and effective agents than miltefosine against N. fowleri for further development.