# High throughput chemoenzymatic synthesis of antimalarial compounds

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $195,000

## Abstract

PROJECT SUMMARY
Malaria continues to pose a significant threat to human health with over 200 million cases each year and nearly
500,000 deaths worldwide. These staggering numbers illustrate the magnitude of this parasitic disease despite
preventive programs such as insecticide-treated nets and available drugs. Thus, combatting this disease will
require a multiprong approach that includes preventative measures such as vaccines and strategies to minimize
transmission as well as effective treatments. Although recent advances in a malaria vaccine and social programs
are poised for success, the efficacy of available small molecule drugs is threatened by the exponential rise in
drug-resistance in Plasmodium falciparum (P. falciparum). For example, chloroquine resistance has steadily
spread with the broad distribution of this drug first introduced in 1945 and resistance has already emerged toward
artemisinin-based combination therapy (ACT) first administered in the mid-2000's. Based on this trajectory, there
is a dire need for the development of novel small molecule antimalarial drugs.
 Historically, natural plant metabolites have provided the basis for potent antimalarial drugs. For example,
quinine, the first antimalarial drug which is isolated from the bark of the Cinchona tree, provided the structural
basis for the most widely used small molecule malaria treatment in history, chloroquine. Similarly, artemisinin is
also a plant natural product, which has become the favored treatment for falciparum malaria and is often
administered along with different classes of antimalarial drugs including mefloquine and amodiaquine. The
complex structures of natural products, like artemisinin, can complicate or even completely derail the
development of natural metabolites with promising antimalarial activity as therapeutic agents. This has left potent
antiplasmodial natural products underexplored. For example, plant natural products, such as
naphthylisoquinoline alkaloids and aryl anthraquninones, display potency against P. falciparum and selectivity
for the parasite over human cell lines that exceeds chloroquine, yet restricted access to the natural compounds
and synthetic analogs has limited the development of these compounds as medicines.
 To overcome the challenges associated with constructing complex biaryl natural products such as
naphthylisoquinoline alkaloids and aryl anthraquinones through traditional synthesis, we propose a convergent
chemoenzymatic approach toward this class of molecules. The biosynthetic pathways related to
naphthylisoquinone and aryl anthraquinone plant metabolites have not been identified, therefore, we envision
adapting enzymes associated with bacterial and fungal biosynthetic pathways for this purpose. We will employ
a high throughput protein engineering strategy to tune and ensure access to enzymes with suitable substrate
scope and desired site- and atroposelectivity. With the ability to rapidly generate targeted natural product cl...

## Key facts

- **NIH application ID:** 10526962
- **Project number:** 1R21AT011782-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Alison Narayan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526962

## Citation

> US National Institutes of Health, RePORTER application 10526962, High throughput chemoenzymatic synthesis of antimalarial compounds (1R21AT011782-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10526962. Licensed CC0.

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