Tetrahydro-1,3-oxazepines via Intramolecular Amination of Cyclopropylmethyl Cation

An efficient synthesis of tetrahydro-1,3-oxazepines was developed involving the regioselective intramolecular amination of cyclopropylmethyl cation. The cation was generated by the abstraction of one imidate group in bis-imidate bearing a carbocation-stabilizing substituent. Using 1,1,2,3-tetrasubstituted cyclopropane substrates, highly diastereoselective intramolecular amination to <i>trans</i>-tetrahydro-1,3-oxazepines was achieved. The resulting tetrahydro-1,3-oxazepines were transformed to the homoallylamine derivatives in high yields

2‑Vinyl Threoninol Derivatives via Acid-Catalyzed Allylic Substitution of Bisimidates

A diastereoselective synthesis of 4-vinyl oxazolines <i>syn-</i><b>2</b> was developed based on an acid-catalyzed cyclization of bistrichloroacetimidates (<i>E</i>)-<b>1</b>. The reaction likely involves an allyl carbenium ion intermediate in which the adjacent stereocenter directs the stereoselectivity for C–N bond formation. Oxazolines <i>syn-</i><b>2</b> were transformed to C-quaternary threoninol, threoninal, and threonine derivatives which can be further incorporated into complex natural compounds

Exploring the Binding Pathway of Novel Nonpeptidomimetic Plasmepsin V Inhibitors

Predicting the interaction modes and binding affinities of virtual compound libraries is of great interest in drug development. It reduces the cost and time of lead compound identification and selection. Here we apply path-based metadynamics simulations to characterize the binding of potential inhibitors to the Plasmodium falciparum aspartic protease plasmepsin V (plm V), a validated antimalarial drug target that has a highly mobile binding site. The potential plm V binders were identified in a high-throughput virtual screening (HTVS) campaign and were experimentally verified in a fluorescence resonance energy transfer (FRET) assay. Our simulations allowed us to estimate compound binding energies and revealed relevant states along binding/unbinding pathways in atomistic resolution. We believe that the method described allows the prioritization of compounds for synthesis and enables rational structure-based drug design for targets that undergo considerable conformational changes upon inhibitor binding

Semisynthesis of Libiguin A and Its Analogues by Trans-Lactonization of Phragmalin

Libiguins are limonoids with highly potent sexual activity enhancing effects, originally isolated from the Madagascarian Meliaceae species Neobeguea mahafalensis, where they exist in only minute quantities. Their low natural abundance has hampered mapping of their biological effects. Here we describe an approach to the semisynthesis of libiguin A and its close analogues <b>1</b>–<b>3</b> starting from phragmalin, which is a limonoid present in high amounts in a commercially cultivated Meliaceae species, Chukrasia tabularis, allowing the preparation of libiguins in appreciable quantities

Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

Antimalarial hit <b>1</b><i><b>SR</b></i> (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of <b>1</b><i><b>SR</b></i> bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues <b>17</b> and <b>18</b> as low nanomolar inhibitors of both, plasmepsin Plm IV activity and <i>P. falciparum</i> growth in erythrocytes

Fragment-Based Discovery of 2‑Aminoquinazolin-4(3<i>H</i>)‑ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV

2-Aminoquinazolin-4­(3<i>H</i>)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial fragment hit optimization led to a submicromolar inhibitor, which was cocrystallized with Plm II to produce an X-ray structure of the complex. The structure showed that 2-aminoquinazolin-4­(3<i>H</i>)-ones bind to the open flap conformation of the enzyme and provided clues to target the flap pocket. Further improvement in potency was achieved via introduction of hydrophobic substituents occupying the flap pocket. Most of the 2-aminoquinazolin-4­(3<i>H</i>)-one based inhibitors show a similar activity against digestive Plms I, II, and IV and >10-fold selectivity versus CatD, although varying the flap pocket substituent led to one Plm IV selective inhibitor. In cell-based assays, the compounds show growth inhibition of Plasmodium falciparum 3D7 with IC₅₀ ∼ 1 μM. Together, these results suggest 2-aminoquinazolin-4­(3<i>H</i>)-ones as perspective leads for future development of an antimalarial agent

Pintavedenoton suhteen kriittisimmät väyläosuudet liikenteen ja väylänpidon kannalta

<i>N</i>-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of <i>E. coli</i> leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure–activity relationship analysis. Enzymatic assays revealed that <i>N</i>-leucinyl benzenesulfonamides display remarkable selectivity for <i>E. coli</i> leucyl-tRNA synthetase compared to <i>S. aureus</i> and human orthologues. The simplest analogue of the series, <i>N</i>-leucinyl benzenesulfonamide (R = H), showed the highest affinity against <i>E. coli</i> leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, <i>E. coli</i> ATCC 25922), which renders it as a promising template for antibacterial drug discovery