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Bis-benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens
Christopher A Rice1, Beatrice L Colon2, Mehmet Alp3
1Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.
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.
Insights
New amidino derivatives show promise as potent drugs against Naegleria fowleri, the cause of fatal primary amoebic meningoencephalitis (PAM). These compounds offer hope for treating this neglected disease with high mortality rates.
Area of Science:
- Infectious Diseases
- Drug Discovery
- Parasitology
Background:
- Naegleria fowleri causes primary amoebic meningoencephalitis (PAM), a rapidly fatal infection with a 99% mortality rate.
- Current therapeutic options for PAM are limited, necessitating the development of new, effective treatments.
- Amidino derivatives are a promising chemotype, demonstrating efficacy against various pathogens and the ability to cross the blood-brain barrier.
Purpose of the Study:
- To identify novel drug candidates for Naegleria fowleri infections.
- To validate new in vitro assays for high-throughput screening of potential therapeutics.
- To explore the potential of amidino derivatives as a treatment for primary amoebic meningoencephalitis.
Main Methods:
- Development and validation of two in vitro assays for drug discovery against N. fowleri.
- Screening of over 150 amidino derivatives across diverse structural classes.
- Determination of inhibitory concentrations (IC50) and selectivity indices for hit compounds.
Main Results:
- Identification of two potent hit series of amidino derivatives with nanomolar (nM) potency against N. fowleri.
- The most potent compound, DB173, exhibited an IC50 of 177 nM.
- Ten additional analogues demonstrated IC50 values below 1 μM, with several showing good selectivity.
Conclusions:
- Mono- and diamidino derivatives represent a viable lead for optimizing new drugs against N. fowleri.
- These compounds show significantly higher potency than existing treatments like pentamidine.
- The identified hits offer potential for developing effective treatments for central nervous system infections caused by N. fowleri.
