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NIH grant 1R01AI192615-01A1: Optimization of the Pyrroloiminoquinone Scaffold for Malaria and Babesiosis Treatment
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: CHOUKRI BEN MAMOUN. Award: $783811.
Start: 2026-07-23T00:00:00.
Project Summary
The goal of this collaborative research program is to identify antimalarial and antibabesial clinical candidates
among analogues of the pyrroloiminoquinone alkaloids (PIQs), an underexplored class of natural products with
potent activity against Plasmodium falciparum, the causative agent of the deadliest form of human malaria. Drug
resistance remains the leading factor hampering global efforts aimed at controlling malaria infection, lowering
mortality rates and reducing the cost of treatment. Countering drug resistance requires the development of new
classes of chemicals not previously used in malaria therapy, and implementation of novel therapeutic strategies
for optimal use of these chemicals. Babesiosis, caused by tick-borne Babesia species—another group of
intraerythrocytic parasites closely related to malaria parasites and belonging to the same phylum—highlights an
urgent need for targeted chemotherapeutics agents, as its prevalence is increasing in the US and worldwide and
there are no effective treatments. Preliminary data from our laboratories indicate that PIQs have strong potential
as novel antimalarial and antibabesial agents. Specifically, our data demonstrate that (i) PIQ natural products
and unnatural analogues have potent activity against blood stages of both drug-sensitive and drug-resistant P.
falciparum strains, with IC50 values in the low nanomolar range; (ii) many of these compounds display similarly
potent activity against B. duncani and B. divergens, two Babesia species; (iii) PIQs are amenable to simple,
rapid, and convergent syntheses, allowing for the generation of numerous analogues that retain potent
antiparasitic activity; (iv) they are safe, with favorable therapeutic indices; (v) their heterocyclic structures provide
excellent starting physicochemical properties; and (vi) they likely act via novel mechanisms, thus offering a
unique therapeutic approach. Building upon this body of data, we propose aims to explore the structure-activity
relationship (SAR) of these compounds, evaluate their in vitro and in vivo efficacy and safety, and elucidate their
mode of action. In Aim 1, we will assess the biological activity and pharmacological properties of lead PIQ
analogues already in hand, focusing on their ability to inhibit growth of drug-sensitive and drug-resistant malaria
parasites within human red blood cells, to block sexual differentiation and transmission to mosquitoes, and to
eliminate lethal malaria infection in mice; similar experiments will be conducted for babesiosis. In Aim 2, we will
employ a flexible chemical synthesis design that permits access to many diverse PIQ-type compounds, with the
goal of optimizing for potency and pharmacological properties. Promising compounds will be further evaluated
for safety and efficacy in animal models of malaria and babesiosis. In Aim 3, we will elucidate the mode of action
of these compounds and potential parasite resistance mechanisms using advanced chemical biology and
systems biology approaches. This project is highly relevant to human health, with the potential to deliver new
preclinical antimalarial and antibabesial leads based on a novel class of compounds, addressing critical gaps in
the treatment of these parasitic diseases.document fetched 2026-08-02 08:24