Design, Synthesis and Biological Evaluation of Antileishmanial Azaheterocyclic Compounds as Inhibitors of the Parasitic Exokinase CK1 (casein kinase 1)

Home Institution: Gülşah Bayraktar, Ege University Turkey, Izmir, Turkey

Hosting Institution: Professor Pascal MARCHAND, IICiMed of Nantes University - France

Goals. Considering the side effects, high toxicities, and the high rate of treatment failure of existing drugs; novel, selective, safe and cost-effective medications are urgently needed. Among the molecular targets to tackle Leishmaniasis, CK1 enzyme attracts attention. The hosting lab has several studies on the design, synthesis and biological evaluation of CK1 inhibitors as antileishmanial agents. IICiMed team has identified the structural requirements to target L-CK1.2 with imidazo[1,2-a]pyrazine derivatives. On the other hand, the group in Turkey has been working on the design, synthesis and bioactivity studies for PTR1 inhibitors and has introduced thiazolopyrimidine scaffold with promising in vivo antileishmanial effect. To explore the chemical diversity of the antiparasitic series, French and Turkish collaborators assumed that the expertise of the two groups could be mixed with success by designing thiazolopyrimidines endowed with the suitable pharmacophoric part responsible of Leishmania CK1 inhibition. The best inhibitors will be selected step by step through different biological filters: 

•  selectivity toward human CK1 
• - toxicity (good selectivity index) 
•  antileishmanial activity on visceral and cutaneous strains. 

It is very important to consider the toxicity in the early stage of the strategy for the best choice of the compounds engaged in phenotypic parasite screening. 

To anticipate the mobility and for effective collaboration, a set of 10 thiazolopyrimidines already synthesized in the applicant’s Lab was received mid-March at the host’s Lab to test their antileishmanial activity on Leishmania donovani and L. major strains to complete the biological profile determined in Ege University - Turkey. 

In parallel to the phenotypic approach, the starting period of the applicant’s stay in IICiMed Lab will be dedicated to the discussion of the design of new thiazolopyrimidine-based compounds with suitable substitution to obtain L-CK1.2 inhibition. Taking into account those remarks, the applicant will synthesize the first examples of pyridyl derivatives of the series to validate the strategy. 

Bazin, M.-A.; Cojean, S.; Pagniez, F.; Bernadat, G.; Cavé, C.; Ourliac-Garnier, I.; Nourrisson, M.-R.; Morgado, C.; Picot, C.; Leclercq, O.; Baratte, B.; Robert, T.; Späth, G.F.; Rachidi, N.; Bach, S.; Loiseau, P.M.; Le Pape, P.; Marchand, P. In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition. Eur. J. Med. Chem. 2021, 210, 112956; doi: 10.1016/j.ejmech.2020.112956.