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

• Main Authors: Ahmed H. E. Hassan, Trong-Nhat Phan, Seolmin Yoon, Cheol Jung Lee, Hye Rim Jeon, Seung-Hwan Kim, Joo Hwan No, Yong Sup Lee
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2021-01-01
• Series: Journal of Enzyme Inhibition and Medicinal Chemistry
• Subjects: antileishmanial agents; promastigotes; amastigotes; repurposing; molecular docking; inositol phosphoceramide synthase; ipcs; sphingomyelin
• Online Access: http://dx.doi.org/10.1080/14756366.2021.1969385

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.