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Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani
- Source :
- Journal of Enzyme Inhibition and Medicinal Chemistry, article-version (VoR) Version of Record, Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1922-1930 (2021)
- Publication Year :
- 2021
- Publisher :
- Informa UK Limited, 2021.
-
Abstract
- A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.
- Subjects :
- Eudysmic ratio
Pyrrolidines
Stereochemistry
Phosphorylcholine
Antiprotozoal Agents
Drug Evaluation, Preclinical
Molecular Conformation
Palmitates
repurposing
Leishmania donovani
amastigotes
RM1-950
Pyrrolidine
sphingomyelin
Structure-Activity Relationship
chemistry.chemical_compound
Amide Synthases
IPCS
Drug Discovery
Humans
Inositol
Homology modeling
Amastigote
Pharmacology
biology
Antileishmanial agents
molecular docking
General Medicine
biology.organism_classification
Sphingolipid
Sphingomyelins
Molecular Docking Simulation
chemistry
inositol phosphoceramide synthase
Therapeutics. Pharmacology
promastigotes
Enantiomer
Research Article
Research Paper
Subjects
Details
- ISSN :
- 14756374 and 14756366
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....0b19cb64eb265e2bfbe864c8accb7402