{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:28:09Z","timestamp":1760059689960,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea government (MIST)","award":["RS-2024-00333842"],"award-info":[{"award-number":["RS-2024-00333842"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives:\u00a0Naegleria 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.<\/jats:p>","DOI":"10.3390\/ph18070984","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:55:43Z","timestamp":1751442943000},"page":"984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of Cyclopentane-Based Phospholipids as Miltefosine Analogs with Superior Potency and Enhanced Selectivity Against Naegleria fowleri"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-6281","authenticated-orcid":false,"given":"Ahmed H. E.","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u01b0\u01a1ng Giang","family":"L\u00ea","sequence":"additional","affiliation":[{"name":"Department of Parasitology and Tropical Medicine, Department of Convergence Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"},{"name":"Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tu\u1ea5n C\u01b0\u1eddng","family":"V\u00f5","sequence":"additional","affiliation":[{"name":"Department of Parasitology and Tropical Medicine, Department of Convergence Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"},{"name":"Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minji","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joo Hwan","family":"No","sequence":"additional","affiliation":[{"name":"Chemical and Structural Biology of Pathogens, Institut Pasteur Korea, Seongnam-si 13488, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-5783","authenticated-orcid":false,"given":"Mohamed H.","family":"Aboutaleb","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaehoon","family":"Sim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea"},{"name":"Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Institute of Regulatory Innovation through Science, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6734-1673","authenticated-orcid":false,"given":"Byoung-Kuk","family":"Na","sequence":"additional","affiliation":[{"name":"Department of Parasitology and Tropical Medicine, Department of Convergence Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"},{"name":"Institute of Health Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6523-6979","authenticated-orcid":false,"given":"Yong Sup","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea"},{"name":"Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6677","DOI":"10.1128\/AAC.01293-15","article-title":"Naegleria fowleri: Pathogenesis, diagnosis, and treatment options","volume":"59","author":"Grace","year":"2015","journal-title":"Antimicrob. 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