# Synthetic studies and antimalarial activities of bastimolides and related polyketides

> **NIH NIH R03** · UNIVERSITY OF IOWA · 2024 · $83,831

## Abstract

Project Summary/Abstract
The World Health Organization estimated that 2016 and 2017 each saw an increase of 2–4 million cases of
malaria worldwide, rising to a total of 241 million cases and 627,000 deaths by 2020, mostly among small
children. These resurging numbers signal that the effective treatment of malaria is under threat from the
development of drug resistance in Plasmodium falciparum and related malaria parasite species.
Consequently, combatting resistance is a critical priority and requires continued effort in discovery and
development of new antimalarial drug candidates with novel mechanisms of action.
Natural product chemistry has had a dramatic impact in treatment of infectious disease. Bastimolide A is a
recently discovered natural product that shows noteworthy activity (IC50 80–270nm) against resistant strains
of P. falciparum, and its polyketide structure is unique among current clinical and investigational antimalarial
drugs, suggesting a novel mechanism of action. If confirmed, this would strongly impact the field of
antimalarial drug discovery, offering a new avenue to address the critical priority of combatting drug
resistance.
Our specific aims in this proposal are (a) to synthesize bastimolide A and analogs, including chemoproteomics
probes, and (b) to evaluate their antiplasmodial potency, improve pharmacological properties, and identify
protein(s) and lifecycle stage(s) targeted. The synthetic aims will exploit efficient new synthetic methods
developed in the Friestad labs, including further development of a novel asymmetric catalysis approach to
1,2-difunctional compounds, and further expansion of a programmed synthesis approach to access 1,5-
polyols with complete control of challenging remote stereochemical relationships. The biological evaluation
of bastimolide A and analogs will employ resistant strains of P. falciparum, and for this aim, the extensive
experience with assessment and development of novel antimalarial drug leads in the Chakrabarti labs is
ideally suited. Measurement of EC50 versus chloroquine-resistant P. falciparum Dd2 will identify hits and verify
activity of chemoproteomics probes; the latter will allow isolation and identification of a biological target for
bastimolide A. Further screens of analogs will entail cross-resistance profiling versus geographical isolates
and evaluation of pharmacological properties such as aqueous solubility, LogD, permeability (PAMPA),
plasma protein binding and microsomal stability. A reiterative approach will be used, with feedback from initial
analogs guiding the selection of higher-priority analogs to prepare during the second year of the proposed
two-year funding period. The R03 funding requested will permit access to the preliminary results needed to
assess the viability of a more extensive project that would be competitive for funding via R21 or R01
mechanism.

## Key facts

- **NIH application ID:** 10884252
- **Project number:** 5R03AI171379-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** GREGORY K FRIESTAD
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $83,831
- **Award type:** 5
- **Project period:** 2023-07-07 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884252

## Citation

> US National Institutes of Health, RePORTER application 10884252, Synthetic studies and antimalarial activities of bastimolides and related polyketides (5R03AI171379-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10884252. Licensed CC0.

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