title: Bis-benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens.
abstract: Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri.
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Rice
authors.affiliation: Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Beatrice L
authors.initials: BL
authors.lastname: Colon
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandogan, Ankara, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Alp
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandogan, Ankara, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Göker
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA dkyle@health.usf.edu.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
mesh_terms: D000562:Amebiasis / Q000188:drug therapy / Q000382:microbiology; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000633:toxicity; D001562:Benzimidazoles / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020808:Central Nervous System Protozoal Infections / Q000188:drug therapy / Q000382:microbiology; D057166:High-Throughput Screening Assays; D051379:Mice; D016848:Naegleria fowleri / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D001562:Benzimidazoles