Imidazolopiperazines as next-generation antimalarial agents: a scoping review of efficacy, mechanisms of action and resistance; prospects for future development.

BACKGROUND

The emergence and spread of antimalarial drug resistance have created an urgent need for novel therapeutic agents. Imidazolopiperazines (IZPs) represent a promising new class of compounds with broad activity against multiple stages of the malaria parasite life cycle.

OBJECTIVE

This scoping review aimed to map current evidence on the efficacy, mechanisms of action, resistance determinants, and clinical development of IZPs, particularly KAF156 (Ganaplacide) and its analog GNF179, to assess their potential as next-generation antimalarial agents.

ELIGIBILITY CRITERIA: Peer-reviewed studies of clinical, in vivo, or in vitro were included if they investigated IZPs for antimalarial efficacy, mechanisms of action or resistance, safety, or comparison with other drugs. Only English-language publications were considered.

SOURCES OF EVIDENCE: Searches were performed in PubMed, Google Scholar, ClinicalTrials.gov, and organizational databases (MMV and Novartis). Citation mapping using Litmaps identified additional related studies. The final search was completed on December 20, 2024.

CHARTING

METHODS

Two reviewers independently screened, selected, and extracted data using a form capturing study characteristics, compounds, parasite stages, efficacy, mechanisms of action or resistance, and safety. Discrepancies were resolved by consensus. Data were synthesized descriptively and summarized by study type, parasite stage, compound, and outcome.

RESULTS

IZPs demonstrate potent activity against asexual blood stages, liver stages, and gametocytes. Proposed mechanisms of action include mitochondrial disruption, sodium pump inhibition, and interference with protein trafficking. Resistance-associated mutations have been identified in genes such as Pfugt, Pfact, and Pfcarl. Clinical trials of KAF156, including combination therapy with lumefantrine, report favorable efficacy, safety, and tolerability, with side effects that are generally mild and manageable.

CONCLUSION

IZPs hold strong potential as next-generation antimalarial agents, particularly for combination therapies. Future research should prioritize clarifying mechanisms of action, monitoring resistance pathways, and optimizing clinical deployment strategies to address the ongoing challenges of antimalarial drug resistance and support malaria elimination goals.