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| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
RSC medicinal chemistry
2025
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| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40547259/ |
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Table of Contents:
- Pharmacophore-guided optimization of the hit compound CTN1122 in the design of promising imidazo[1,2-]pyrazine derivatives targeting the casein kinase 1 for antileishmanial therapy. Tisseur, Lhana Logé, Cédric Cojean, Sandrine Gassama, Khadidiatou Karcher, Lilian Pagniez, Fabrice Cavé, Christian Bernadat, Guillaume Loiseau, Philippe M Bach, Stéphane Thiéfaine, Jérôme Bonnet, Justine Picot, Carine Tomasoni, Christophe Leclercq, Olivier Baratte, Blandine Robert, Thomas Le Pape, Patrice Rachidi, Najma Bazin, Marc-Antoine Marchand, Pascal Our research group identified CTN1122, an imidazo[1,2-]pyrazine derivative, as a promising antileishmanial agent targeting intramacrophage amastigotes of and . CTN1122 selectively inhibits 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-]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 potency (IC = 0.20 μM for ; 0.16 μM for ) alongside enhanced L-CK1.2 inhibition (IC = 0.384 μM), with no significant mammalian cytotoxicity.