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
| Autor: | Hye Rim Jeon, Trong-Nhat Phan, Ahmed H.E. Hassan, Seolmin Yoon, Yong Sup Lee, Cheol Jung Lee, Seung-Hwan Kim, Joo Hwan No |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | 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) |
| ISSN: | 1475-6374 1475-6366 |
| DOI: | 10.1080/14756366.2021.1969385 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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