An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

Abstract

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphin-gosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b] pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.

Proline-Based Carbamates as Cholinesterase Inhibitors

“…These moieties interact with a number of enzymes/receptors and, by means of these target sites, they are able to affect the biological response. Therefore, the reason for the widespread occurrence of amides and carbamates among new biologically active compounds is obvious [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Carbamate-like compounds can be considered as essential cholinesterase inhibitors (ChEIs) [ 1 , 16 , 17 , 18 ].…”

Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti‐inflammatory activity

“…We first evaluated the SphK2‐inhibitory activity of the 16 compounds selected from our previous screen of SphK1 inhibitors . Synthesis and structural characterization of compounds 1–16 has been described and their structures are shown in Table . SphK2 inhibitors were evaluated in a 384‐well high‐throughput format assay as described .…”

“…We have recently described two types of structural scaffolds for developing new SphK1 inhibitors . These new compounds were obtained through virtual screening, being the most active compounds of these series (molecules 2–4 (Table )).…”

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain

“…Melting point (Mp or mp) values of prepared intermediates and final compounds, respectively, were determined on the Kofler hot plate apparatus HMK (Franz Kustner Nacht GK, Dresden, Germany) and left uncorrected. The mps of some intermediates were already published, i.e., 3a : 102–104 °C [ 64 ]; 3b : 111–112 °C [ 64 ] and 113–114 °C [ 65 ], respectively; 3d : 53–55 °C [ 64 ]; 3e : 168 °C [ 64 ] and 160–162 °C [ 66 ], respectively; 3f : 158 °C [ 67 ], 157–158 °C [ 68 , 69 ] and 160–161 °C [ 64 ], respectively; 3h : 87–88.5 °C [ 64 ]; 4a : 99–103 °C [ 70 ]; 4b : 108–110 °C [ 71 ]; 4d : 80–86 °C [ 70 ]; 4e : 200–201 °C [ 72 ].…”