STSM - Synthesis of the clickable heteroaromatic plasmodione analogue IT11 for bioimaging and proteomics. - IOANNIS TOLIS

Description of the STSM main achievements and planned follow-up activities 

Description and assessment of whether the STSM achieved its planned goals and expected outcomes, including specific contribution to Action objective and deliverables, or publications resulting from the STSM. Agreed plans for future follow-up collaborations shall also be described in this section. 

(max. 500 words) 

The main objective of this STSM was to receive advanced training in medicinal chemistry and chemical biology techniques while contributing to the development of photoaffinity-based protein profiling (AfBPP) probes. These probes are analogues of antiparasitic compounds designed in the host group, for proteomic and bioimaging studies in Toxoplasma gondii and Schistosoma mansoni. The mobility was carried out at the European School of Chemistry, Polymers and Materials (ECPM), in the research unit UMR7042 CNRS-Unistra-UHA (LIMA), where I worked within an interdisciplinary research environment and gained valuable practical experience in modern synthetic methodologies. 

During the STSM, I contributed to the synthesis and characterization of compounds related to 3-benzylmenadione-derived AfBPP probes. The work involved multi-step organic synthesis, reaction optimization, purification using chromatographic techniques, and structural characterization through analytical methods such as NMR spectroscopy and mass spectrometry. Through these activities, I acquired practical expertise in medicinal chemistry workflows and strengthened my understanding of the design and preparation of chemical tools for biological investigations. 

The planned objectives of the STSM were successfully achieved. The research activities enabled substantial progress in the preparation of key synthetic intermediates and target molecules required for subsequent biological studies. In addition, the training provided hands-on experience in techniques that were not available at my home institution, significantly enhancing my scientific skills and research capabilities. The mobility also facilitated the exchange of knowledge between the host and home institutions and promoted the transfer of expertise in the fields of synthetic chemistry and chemical biology. 

The STSM contributed directly to the objectives of COST Action CA21111 by fostering international collaboration, supporting the training and mobility of an Early Career Researcher, and promoting interdisciplinary research approaches for the discovery and characterization of biologically active compounds. The knowledge and experience in organic and medicinal chemistry gained during the stay will be transferred to my home institution and will support future research activities within the COST network. In the home group, my improved skills will be applied in future research activities related to other series of antimalarial compounds in medicinal chemistry and chemical biology. Future efforts will focus on the development of new synthetic strategies and approaches aimed at expanding the available chemical tools for target identification studies. 

In the host group, the synthesis of the clickable 3-benzyl-6-fluoromenadione alkyne 6 (IT11) derivative will be pursued in order to complement the current series of AfBPP probes and further strengthen the structure–activity and structure–target relationship investigations. The completion of this synthetic work, together with the biological evaluation of the synthesized probes, is expected to provide a more comprehensive dataset for the investigation of 3-benzylmenadione-derived antiparasitic compounds to identify the interactomes of antiparasitic 3-benzylmenadiones in various human and animal parasites. The combination of synthesis, chemical biology, and biological data will contribute to a more complete understanding of the molecular targets and mechanisms of action of these compounds. Depending on the outcome of the biological studies, the collected results may form the basis of a future scientific publication presenting a comprehensive evaluation of this family of clickable antiparasitic probes. 

(1) Iacobucci I., I., Monaco V., Dupouy B., Hovasse A., Keumoe R., Cichocki B., Elhabiri M., Blandin S. A., Meunier B., Strub J.-M., Monti M., Cianférani S., Schaeffer-Reiss C., Davioud-Charvet E. Proteomic profiling of antimalarial plasmodione using 3-benz(o)ylmenadione affinity-based probes. ChemBioChem 2024, 25(15):e202400187. doi: 10.1002/cbic.202400187. 

(2) Trometer N., Roignant M., Davioud-Charvet E. An efficient multigram scale synthesis of 7-substituted-3-methyltetral-1-ones and 6-fluoromenadione. Org. Process Res. Dev. 2022, 26, 4, 1152–1164. doi: 10.1021/acs.oprd.1c00421. 

(3) Cichocki B., Khobragade V., Donzel M., Cotos L., Blandin S., Schaeffer-Reiss C., Cianférani S., Strub J.-M., Elhabiri M., Davioud-Charvet E. A new class of valuable (pro-)activity-based protein profiling probes: application to the redox-active antimalarial drug, plasmodione. JACSAu 2021, 1, 669-689. doi: 10.1021/jacsau.1c00025 

(4) Dupouy B, Donzel M, Roignant M, Charital S, Keumoe R, Yamaryo-Botté Y, Feckler A, Bundschuh M, Bordat Y, Rottmann M, Mäser P, Botté CY, Blandin SA, Besteiro S, Davioud-Charvet E. 3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies. ACS Infect Dis. 2024 Oct 11;10(10):3553-3576. doi: 10.1021/acsinfecdis.4c00304. 

(5) Dupouy B, Cotos L, Binder A, Slavikova L, Rottmann M, Mäser P, Jacquemin D, Ganter M, Davioud-Charvet E., Elhabiri M. Click Coupling of Flavylium Dyes with Plasmodione Analogues: Towards New Redox-Sensitive Pro-Fluorophores. Chemistry 2025, 31(6):e202403691. doi: 10.1002/chem.202403691