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© Research
Publication : RSC medicinal chemistry

Pharmacophore-guided optimization of the hit compound CTN1122 in the design of promising imidazo[1,2-a]pyrazine derivatives targeting the casein kinase 1 for antileishmanial therapy.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in RSC medicinal chemistry - 05 Jun 2025

Tisseur L, Logé C, Cojean S, Gassama K, Karcher L, Pagniez F, Cavé C, Bernadat G, Loiseau PM, Bach S, Thiéfaine J, Bonnet J, Picot C, Tomasoni C, Leclercq O, Baratte B, Robert T, Le Pape P, Rachidi N, Bazin MA, Marchand P

Link to Pubmed [PMID] – 40547259

Link to DOI – 10.1039/d5md00257e

RSC Med Chem 2025 Jun; ():

Our research group identified CTN1122, an imidazo[1,2-a]pyrazine derivative, as a promising antileishmanial agent targeting intramacrophage amastigotes of Leishmania major and Leishmania donovani. CTN1122 selectively inhibits Leishmania casein kinase 1 (L-CK1.2) with a favorable safety profile. Docking studies based on a homology model highlighted key pharmacophoric elements: a 4-pyridyl group at C3, crucial for hydrogen bonding with leucine 90 in the ATP-binding site, and a 4-fluorophenyl moiety at C2, fitting into a hydrophobic pocket. In order to validate these findings, 14 analogs were synthesized with targeted modifications on the imidazo[1,2-a]pyrazine core structure. Three probed the C8 position, three evaluated the impact of C2 substitution, six assessed the C3 4-pyridyl group, and two combined changes at C8 and C3. The study confirmed the critical role of C2 and C3 substituents, as their absence significantly reduced L-CK1.2 inhibition and antileishmanial activity. Additionally, the nitrogen’s position within the pyridine ring at C3 proved essential: compound 23, with a meta-pyridyl group, was inactive. Notably, compound 30 exhibited the highest antileishmanial in vitro potency (IC50 = 0.20 μM for L. major; 0.16 μM for L. donovani) alongside enhanced L-CK1.2 inhibition (IC50 = 0.384 μM), with no significant mammalian cytotoxicity.