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

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