ADMET studies on novel thiazolidinone derivatives with promising in vitro anti-Leishmanial activity.

Home institution. Name of the applicant: Sara Luelmo Moya. Affiliation: Host-Parasite Interactions group form I3S (Institute for Research and Innovation in Health) Country: Portugal

Host institution: Name of the host lab PI: Theodora Calogeropoulou. Affiliation: Institute of Chemical Biology at the National Hellenic Research Foundation (NHRF). Country: Greece

Summary

Leishmaniasis is a parasitic vector-borne disease that is a prime example of the importance of the One Heath concept [1-2]. The search for new drugs for human and/or veterinary use is necessary for improved management of the disease [2]. After primary activity and toxicity assessment, before in vivo activity evaluation in murine models, complementary preclinical studies are needed. Among these

ADMET information ensures the maximum likelihood of success in the subsequent relevant infection models. Thus, the purpose of the present STSM is to perform in vitro ADMET and pharmacokinetic studies (PK) on selected thiazolidinone derivatives that have undergone rigorous optimisation through the obtainment of structure-activity relations based on in vitro screening for activity and toxicity for Leishmania. This joint program between the groups of T Calogeropoulou and A. Cordeiro da Silva resulted in molecules with similar or superior activity to miltefosine, the only orally available drug approved for the management of Leishmania infection. The five most potent derivatives will be evaluated for microsomal stability and CYP enzyme inhibition to select the most appropriate for SNAP-PK evaluation. The current STSM will expand the knowledge of the applicant on in vitro ADMET experiments and analysis of plasma samples UPLC-MS/MS.

The goals of this STSM proposal are to perform in vitro ADMET and pharmacokinetic studies (PK) on selected thiazolidinone derivatives. Five derivatives will be evaluated for microsomal stability and CYP enzyme inhibition to select the most appropriate for SNAP-PK evaluation. This STSM will also promote the career development and scientific upbringing of the applicant through the contact with different aspects of preclinical development associated to in vitro ADMET experiments. This will include the possibility for hands-on application of new techniques and analytical methods and the use of state-of-the-art instrumentation [UPLC-MSn Orbitrap Velos mass spectrometer (Thermo Scientific)and Lionheart FX (BioTek) plate reader.]

1 - WHO. (2023). Leishmaniasis. World Health Organization. Retrieved from https://www.who.int/news-room/fact-sheets/detail/leishmaniasis. Acessed on 10/05/2023.

2 - Palatnik-de-Sousa, C. B., & Day, M. J. (2011). One Health: the global challenge of epidemic and endemic leishmaniasis. Parasit Vectors, 4, 197. doi:10.1186/1756-3305-4-197

3 - Liu, B., Chang, J., Gordon, W. P., Isbell, J., Zhou, Y., & Tuntland, T. (2008). Snapshot PK: a rapid rodent in vivo preclinical screening approach. Drug Discov Today, 13(7-8), 360-367. doi:10.1016/j.drudis.2007.10.014