# Characterization of β‑Carboline Derivatives Reveals a High Barrier to Resistance and Potent Activity against Ring-Stage and DHA-Induced Dormant Plasmodium falciparum

## TL;DR

A new class of β-carboline antimalarials shows strong effectiveness against malaria parasites, including dormant stages, with a high resistance barrier.

## Contribution

Discovery of β-carboline derivatives with potent antimalarial activity and resistance to resistance mechanisms in Plasmodium falciparum.

## Key findings

- PRC1584 and PRC1697 show potent in vitro activity against both ring-stage and dormant Plasmodium falciparum.
- The PfKelch13-C580Y mutation increases susceptibility to PRC1584 but not other mutations.
- The compounds demonstrate a high resistance barrier and no cross-resistance with existing antimalarials.

## Abstract

Malaria, caused by Plasmodium falciparum, remains a major global health challenge, with an estimated 263
million new infections and 597,000 deaths annually. Increasing resistance
to current antimalarial drugs underscores the urgent need for new
therapeutics that target novel pathways in the parasite. We previously
reported a novel class of β-carboline antimalarials, exemplified
by PRC1584, which demonstrated a favorable oral pharmacokinetic profile, in vivo efficacy in Plasmodium berghei-infected mice, and no cross-resistance with other antimalarials
in various P. falciparum strains. In
this study, we demonstrate that PRC1584 exhibits a high resistance
barrier and retains potent activity against fresh Ugandan P. falciparum isolates. PRC1584, along with its more
potent analog PRC1697, demonstrated strong in vitro potency against both actively proliferating ring stages and dihydroartemisinin-induced
dormant stages. Additionally, our study demonstrated that PfKelch13-C580Y
mutation was associated with an increased susceptibility to PRC1584,
whereas PfKelch13-R549T and Pfcoronin-R100 K-E107V mutations were
not associated with this effect. These findings underscore the therapeutic
potential of this new “irresistible” compound class,
support a possible novel mechanism of action, and suggest the future
development of novel ACTs active against resistant parasites by targeting
DHA dormancy, an essential survival mechanism of P.
falciparum.