ACTS 2020 Abstract: Hannah Corman

Investigation of a Series of 1,4-diaryl-pyrazolo-pyridinones as Anti-Leishmanial Agents

Hannah Corman, Douglas A Shoue, Bruce J Melancon, Mary Ann McDowell 

Impact: The first-line chemotherapies used to treat leishmaniasis are highly toxic intravenous antimonials yet drug resistance has begun to develop, causing the use of oral treatment options with high price tags; there is a strong need for new safe and effective chemotherapeutic agents to treat leishmaniasis.

Objectives/Goals: This study was conducted in order to identify novel chemical compounds that exhibit anti-leishmanial activity and to further characterize their efficacy and toxicity in in vitro and in vivo systems in the hopes of future chemotherapeutic developments.

Methods/Study Population: We developed a novel, target-free fluorometric high-throughput screen (HTS) to identify small molecules with anti-leishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVERset-EXP library cassette #5 yielded 210 compounds that killed 80% of parasites. One hundred nine (109) molecular scaffolds were represented within the hit compounds, including the 1,4-diarylo-pyrazolo-pyridinone (1,4-DAPP). A total of 27 novel 1,4-DAPP compounds were synthesized and anti-leishmanial efficacy and host cell toxicity was determined using L. donovani mCherry expressing amastigotes and THP-1 macrophages. Additional pharmacokinetic analyses of a potent 1,4-DAPP compound were conducted.

Results/Anticipated Results: Four experimental compounds had IC50 values less than 5μM, providing similar anti-leishmanial activity to miltefosine. Compound 9279817 had a clearance almost twice the rate of normal hepatic blood flow and had a relatively high volume of distribution, indicating this compound is rapidly cleared and distributes into tissues. In vitro rat liver microsome assays suggest a rapid metabolism of 9279817, and MS/MS results suggest this metabolite is most likely formed via oxidation of the sulfur on the lower aromatic ring.

Discussion/Significance of Impact: This study revealed a novel structural class of compounds that have anti-leishmanial activity. In vitro experiments show compounds with similar efficacy as miltefosine while having significantly less cytotoxicity, suggesting that this class could be further developed as a potential chemotherapeutic.

Hannah Corman abstract

|2020-05-19T09:24:19-04:00May 13th, 2020|Scientific Abstracts|0 Comments

About the Author:

Anna Carrera
Anna Carrera is the research communications manager for Indiana University's Precision Health Initiative, IU School of Medicine Research Affairs and the Indiana Clinical and Translational Sciences Institute. She joined the team in June 2019 after working as a TV news reporter for ten years. She loves sharing stories about the great research being done across the state to improve the health of Hoosiers.

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