Synthetic studies and antimalarial activities of bastimolides and related polyketides

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. 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.

NIH Project details

Drug-based Strategies
Product Development

Jul 2023 — Jun 2025

$82,884

United States