# Optimization of novel phenotypic screening hits for treatment of Malaria

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $737,236

## Abstract

Project Summary.
Malaria remains one of the most serious infectious diseases, globally threatening nearly 50% of the world
population, and leading to >400,000 deaths annually, mostly among young African children. There are no
effective vaccines and the disease is managed through a combination of insecticides and drugs for both
treatment and chemoprevention. The relentless ability of the parasite to acquire drug resistance necessitates
that a continual pipeline of new drug candidates is maintained. We sought to identify novel chemical starting
points for the discovery of new anti-malarial drugs by phenotypic screening against erythrocytic stage P.
falciparum. We undertook a high-throughput screen of a newly acquired (in 2017) 100K chemical library
reasoning that since it was recently purchased it might contain new chemical space that had not been previously
screened. As part of our hit validation process we prioritized hits from the screen based on the following
experimental measures: 1) potency versus the parasite against two cell lines, 2) selectivity versus a human cell
line, 3) novelty of the chemical matter, 4) parasite kill rate (medium and fast kill being desirable) and 5) in vitro
ADME properties including metabolic stability and solubility. We identified 16 chemical series that met our
objectives of novelty and from these have selected 3 series for hit to lead chemistry. These include a piperidine
carboxamide series (Alchm18) that has a moderate rate of kill, good starting potency (P. falciparum 3D7 EC50
<100 nM), and strong starting in vitro and in vivo ADME properties; a a tetrazole-based series (Alchm3) that
shows fast kill kinetics, and a an azetidine amide (Alchm17), with good potency and solubility. We have validated
synthetic strategies for all three series through synthesis of both the parent compound and analogs. The goal
of this proposal is to conduct hit-to-lead chemistry on these three series, to evaluate their biological profiles,
and to perform studies to identify their targets. The strongest series will then be prioritized for full scale lead
optimization. Our project team of Phillips (parasite biology), Ready (medicinal chemistry) and Charman
(ADME/PK) is highly experienced and has a long track record of working together. The project will also be a
collaborative effort with the Medicines for Malaria Venture (MMV) who will provide in kind support and access
to their in vitro and in vivo parasite efficacy models and project oversight. Upon completion of this proposal we
will have substantial new insight into the developability of three new chemical series, we will have validated up
to three additional new anti-malarial targets, and we will have progressed the strongest of our three chemical
series through lead optimization to identify a potential preclinical development candidate.

## Key facts

- **NIH application ID:** 10376179
- **Project number:** 5R01AI155784-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Margaret A. Phillips
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $737,236
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376179

## Citation

> US National Institutes of Health, RePORTER application 10376179, Optimization of novel phenotypic screening hits for treatment of Malaria (5R01AI155784-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10376179. Licensed CC0.

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