Last Updated: 06/10/2025
Development of a new generation of antimalarial drugs for the post-artemisinin era
Objectives
The main objective of this study is to obtain YAT2150 derivatives with a sufficiently favorable selectivity index to allow this new family of antimalarial drugs to begin preclinical development.
The specific objectives are:
- To synthesize YAT2150 derivatives by selective modification of different chemical groups in the original molecule. These analogues will be evaluated for their activity as protein aggregation inhibitors in vitro and in Plasmodium falciparum cultures;
- To characterize the activity of YAT2150 derivatives in P. falciparum and human cell cultures to obtain the respective IC₅₀ (a 50% in vitro growth inhibitory concentration) and CC₅₀ (the 50% cytotoxic concentration) values and thus calculate the corresponding SIs; and
- For those analogues with better selectivity index (SIs), in vivo tests in a murine malaria model will allow estimation of the potential of these compounds to enter a preclinical development process.
The current arsenal of antimalarial drugs is insufficient to make progress toward eradicating the disease, a situation worsened by the alarming evolution of resistance in Plasmodium. This situation requires immediate efforts to discover new, affordable compounds with multiple molecular targets in the pathogen and antiparasitic mechanisms different from those of current drugs.
The BIS (styrylpyridinium) salt YAT2150 has properties that make it very interesting as an antimalarial:
(i) its synthesis is easy and fast (only two steps), which results in an attractive activity/cost ratio since its main clinical development would be in impoverished regions where malaria is endemic;
(ii) its mode of action (inhibition of protein aggregation in the parasite) presumably affects multiple proteins, which would prevent the rapid emergence of resistance, contrary to what happens with most current antimalarials whose targets are one or few gene products;
(iii) it belongs to an unexplored chemical family in which no antimalarial compounds have been described so far, preventing the adaptation by the pathogen of pre-existing resistance mechanisms to similar molecules currently in use;
(iv) preliminary data suggest that YAT2150 could be active against all Plasmodium species that cause human malaria, which would make this drug a pan-malaria treatment;
(v) this molecule emits fluorescence when interacting with its molecular targets in Plasmodium cells, thereby making it a theranostic agent;
(vi) it binds to all stages of the parasite in both the vertebrate host and the mosquito vector;
(vii) it is stable at room temperature for a long time (months); and
(viii) it has a 50% in vitro growth inhibitory concentration (IC₅₀) below 100 nM.
These characteristics position YAT2150 as a promising model molecule for a new generation of antimalarials facing the post-artemisinin era, since resistance to the latter drug (on which the main therapeutic approaches are based) is widespread in Asia, and resistance markers to it have already been identified in Africa and South America.
However, the 50% cytotoxic concentration (CC₅₀) of YAT2150 for human cells results in a selectivity index (SI: CC₅₀/IC₅₀) of less than 100. The prospects for successful clinical development as an antimalarial drug would be significantly improved if the SI could be increased above 100.
Jan 2022
$145,095
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