20 research outputs found
Synthesis and Cytotoxicity of Silicon and Germanium Containing Pyridine Oxime O-Ethers
Silicon and germanium containing pyridine aldoxime, ketoxime and amidoxime O-ethers have been
prepared using phase transfer catalytic systems oxime alkyl halide solid KOH 18-crown-6 benzene and
oxime alkyl halide solid K2CO3 or Cs2CO3 18-crown-6 toluene. Cytotoxic activity of silicon and
germanium containing pyridine oxime O-ethers was tested in vitro on two monolayer tumor cell lines: MG-
22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). O-[3-Yriethylsilylpropyl]- and O-[3-(1-methyl-
1-silacyclopentyl)propyl] oximes of pyridine aldehydes and ketones exhibit high cytotoxicity. Presence of
methyl group in the pyridine ring considerably decreased activity of amidoxime O-ethers. Oxime ethers
containing two elements are essentially inactive. For 2-acetylpyridine oxime ethers the activity increases in
order of alkyl substituents: Et3GeCH2CH2SiMe2CH2 < Et3SiCH2CH2CH2 < (CH2)4SiCH2CH2CH2.
Cytotoxicity of ketoxime O-ethers is considerably lower in comparison with aldoxime O-ethers
Synthesis and Cytotoxicity of Silicon and Germanium Containing Pyridine Oxime O-Ethers
ABSTRAC
Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D.
Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity versus the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This resulted in potent anti-malarials with an up to 50-fold Plm IV/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the P.Β falciparum subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X
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
4-Pyridinio-1,4-Dihydropyridines as Calcium Ion Transport Modulators: Antagonist, Agonist, and Dual Action
A set of six new 4-pyridinio-1,4-dihydropyridine (1,4-DHP) compounds has been synthesized. The calcium channel modulating activity of these compounds was evaluated in an aorta vascular smooth muscle cell line (A7R5), in an isolated rat aortic ring model, and in human neuroblastoma cell lines (SH-SY5Y). The antagonistic effect of these 1,4-DHP was tested by modulating the impact of carbachol-dependent mobilization of intracellular Ca2+ in SH-SY5Y cells. The intracellular free Ca2+ concentration was measured in confluent monolayers of SH-SY5Y cells and A7R5 cells with the Ca2+-sensitive fluorescent indicator Fluo-4 NW. Only four compounds showed calcium channel blocking activity in SH-SY5Y and A7R5 cells as well as in the aortic ring model. Among them, compound 3 was the most active calcium channel antagonist, which had 3 times higher activity on carbachol-activated SH-SY5Y cells than amlodipine. Two of the compounds were inactive. Compound 4 had 9 times higher calcium agonist activity than the classic DHP calcium agonist Bay K8644. The intracellular mechanism for the action of compound 4 using inhibitor analysis was elucidated. Nicotinic as well as muscarinic receptors were not involved. Sarcoplasmic reticulum (ER) Ca2+ (SERCA) stores were not affected. Ryanodine receptors (RyRs), another class of intracellular Ca2+ releasing channels, participated in the agonist response evoked by compound 4. The electrooxidation data suggest that the studied compounds could serve as antioxidants in OS
Π‘ΠΈΠ½ΡΠ΅Π· ΠΈ ΡΠΈΡΠΎΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠ°Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΡ ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»ΠΎΠ²ΠΎΠ³ΠΎ ΡΡΠΈΡΠ° 7Z-Π°ΡΠ΅ΡΠΈΠ»ΠΌΠ΅ΡΠΈΠ»Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-3-ΡΠ΅ΡΠ΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ
ΠΠΎΠ½Π΄Π΅Π½ΡΠ°ΡΠΈΠ΅ΠΉ Π°ΡΠ΅ΡΠΈΠ»ΠΌΠ΅ΡΠΈΠ»Π΅Π½ΠΎΠ²ΠΎΠΉ Π³ΡΡΠΏΠΏΡ Π² ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»ΠΎΠ²ΠΎΠΌ ΡΡΠΈΡΠ΅ 7Z-Π°ΡΠ΅- ΡΠΈΠ»ΠΌΠ΅ΡΠΈΠ»Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-3-ΡΠ΅ΡΠ΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΈ 7Z-Π°ΡΠ΅ΡΠΈΠ»ΠΌΠ΅ΡΠΈΠ»Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈ- ΠΎΠΊΡΠΎ-3-ΡΠ΅ΡΠ΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡ ΠΈ Π² 7Z-Π°ΡΠ΅ΡΠΈΠ»ΠΌΠ΅ΡΠΈΠ»Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ- 3-ΡΠ΅ΡΠ΅ΠΌΠ΅ Ρ Π°ΡΠΈΠ»ΠΌΠ΅ΡΠΎΠΊΡΠΈΠ°ΠΌΠΈΠ½Π°ΠΌΠΈ ΠΈ Π-Π°Π»ΠΊΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»ΠΎΠ²ΠΎΠ³ΠΎ ΡΡΠΈΡΠ° 7Z-(2-Π³ΠΈΠ΄ΡΠΎΠΊΡΠΈΠΌΠΈΠ½ΠΎ)ΠΏΡΠΎΠΏΠΈΠ»ΠΈΠ΄Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-3-ΡΠ΅ΡΠ΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈc- Π»ΠΎΡΡ Π·Π°ΠΌΠ΅ΡΠ΅Π½Π½ΡΠΌΠΈ Π±Π΅Π½Π·ΠΈΠ»Π±ΡΠΎΠΌΠΈΠ΄Π°ΠΌΠΈ, Π° ΡΠ°ΠΊΠΆΠ΅ ΠΏΠΈΡΠΈΠ΄ΠΈΠ»ΠΌΠ΅ΡΠΈΠ»Ρ
Π»ΠΎΡΠΈΠ΄Π°ΠΌΠΈ ΡΠΈΠ½ΡΠ΅- Π·ΠΈΡΠΎΠ²Π°Π½Ρ Π°ΡΠΈΠ»ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΌΠΈΠ½ΠΎ- ΠΈ ΠΏΠΈΡΠΈΠ΄ΠΈΠ»ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΌΠΈΠ½ΠΎΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΠ΅ ΡΡΠΈΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ Π² ΡΠΈΠ½- ΠΈ Π°Π½ΡΠΈ-ΠΈΠ·ΠΎΠΌΠ΅ΡΠ½ΠΎΠΉ ΡΠΎΡΠΌΠ΅.
Π‘ ΠΏΠΎΠΌΠΎΡΡΡ ΡΠ΅Π°Π³Π΅Π½ΡΠ° ΠΠΈΠ»ΡΡΠΌΠ°ΠΉΠ΅ΡΠ° Π²Π²Π΅Π΄Π΅Π½Π° N,N-Π΄ΠΈΠΌΠ΅ΡΠΈΠ»Π°ΠΌΠΈΠ½ΠΎΠΌΠ΅ΡΠΈΠ»Π΅Π½ΠΎΠ²Π°Ρ Π³ΡΡΠΏΠΏΠ° Π² ΠΏΠΎΠ»ΠΎΠΆΠ΅Π½ΠΈΠ΅ 2 ΡΠ΅ΡΠ΅ΠΌΠΎΠ²ΠΎΠ³ΠΎ ΡΠ΄ΡΠ° ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»ΠΎΠ²ΡΡ
ΡΡΠΈΡΠΎΠ² 7Z-[2-(Π°ΡΠΈΠ»- ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΌΠΈΠ½ΠΎ)ΠΏΡΠΎΠΏΠΈΠ»ΠΈΠ΄Π΅Π½]-3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-3-ΡΠ΅ΡΠ΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ. ΠΠΎΡΠ»Π΅- Π΄ΡΡΡΠ°Ρ ΡΡΠ°Π½ΡΡΠΎΡΠΌΠ°ΡΠΈΡ N,N-Π΄ΠΈΠΌΠ΅ΡΠΈΠ»Π°ΠΌΠΈΠ½ΠΎΠΌΠ΅ΡΠΈΠ»Π΅Π½Π·Π°ΠΌΠ΅ΡΠ΅Π½Π½ΡΡ
ΡΠ΅ΡΠ΅ΠΌΠΎΠ² Π³ΠΈΠ΄- ΡΠΎΠΊΡΠΈΠ»Π°ΠΌΠΈΠ½ΠΎΠΌ ΠΏΡΠΈΠ²Π΅Π»Π° ΠΊ ΠΏΠΎΠ»ΡΡΠ΅Π½ΠΈΡ 3Z-[2-(Π°Π½ΡΠΈ-Π°ΡΠΈΠ»ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΌΠΈΠ½ΠΎ)ΠΏΡΠΎΠΏΠΈΠ»ΠΈΠ΄Π΅Π½]-ΡΡΠ΅Ρ-Π±ΡΡΠΎΠΊΡΠΈΠΊΠ°ΡΠ±ΠΎΠ½ΠΈΠ»ΠΌΠ΅ΡΠΈΠ»-4-(5-ΠΌΠ΅ΡΠΈΠ»-4-ΠΈΠ·ΠΎΠΊΡΠ°Π·ΠΎΠ»ΠΈΠ»ΡΡΠ»ΡΡΠΎΠ½ΠΈΠ»)Π°Π·Π΅ΡΠΈΠ΄ΠΈΠ½-2-ΠΎΠ½ΠΎΠ².
ΠΠΎΠ½Π΄Π΅Π½ΡΠ°ΡΠΈΠ΅ΠΉ Π°ΡΠ΅ΡΠΈΠ»ΡΠ½ΠΎΠΉ Π³ΡΡΠΏΠΏΡ Π² ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»ΠΎΠ²ΠΎΠΌ ΡΡΠΈΡΠ΅ 7Z-Π°ΡΠ΅ΡΠΈΠ»- ΠΌΠ΅ΡΠΈΠ»Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-3-ΡΠ΅ΡΠ΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ Ρ 4-Π±ΡΠΎΠΌΡΠ΅Π½ΠΈΠ»- Π³ΠΈΠ΄ΡΠ°Π·ΠΈΠ½ΠΎΠΌ ΡΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½ ΡΠ΅ΡΠ΅ΠΌ Ρ 2-(4-Π±ΡΠΎΠΌΡΠ΅Π½ΠΈΠ»Π³ΠΈΠ΄ΡΠ°Π·ΠΎΠ½ΠΎ)ΠΏΡΠΎΠΏΠΈΠ»ΠΈΠ΄Π΅Π½ΠΎΠ²ΠΎΠΉ Π³ΡΡΠΏΠΏΠΎΠΉ Π² ΠΏΠΎΠ»ΠΎΠΆΠ΅Π½ΠΈΠΈ 7. ΠΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»ΠΎΠ²ΠΎΠ³ΠΎ ΡΡΠΈΡΠ° 7Z-(2-Π³ΠΈΠ΄ΡΠΎΠΊΡ- ΠΈΠΌΠΈΠ½ΠΎ)ΠΏΡΠΎΠΏΠΈΠ»ΠΈΠ΄Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-3-ΡΠ΅ΡΠ΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈcΠ»ΠΎΡΡ Ρ
Π»ΠΎΡΠ°Π½Π³ΠΈΠ΄- ΡΠΈΠ΄ΠΎΠΌ 2-Π±ΡΠΎΠΌΠ±Π΅Π½Π·ΠΎΠΉΠ½ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ ΡΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½ ΡΠ΅ΡΠ΅ΠΌ Ρ 2-(2-Π±ΡΠΎΠΌΠ±Π΅Π½Π·ΠΎΠΈΠ»ΠΎΠΊΡ- ΠΈΠΌΠΈΠ½ΠΎ)ΠΏΡΠΎΠΏΠΈΠ»ΠΈΠ΄Π΅Π½ΠΎΠ²ΠΎΠΉ Π³ΡΡΠΏΠΏΠΎΠΉ Π² ΠΏΠΎΠ»ΠΎΠΆΠ΅Π½ΠΈΠΈ 7.
ΠΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠΉ ΡΠΊΡΠΈΠ½ΠΈΠ½Π³ ΡΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ Π² ΠΎΡΠ½ΠΎΡΠ΅Π½ΠΈΠΈ ΡΠ°ΠΊΠΎΠ²ΡΡ
ΠΈ Π½ΠΎΡΠΌΠ°Π»ΡΠ½ΡΡ
ΠΊΠ»Π΅ΡΠΎΠΊ in vitro ΠΏΠΎΠΊΠ°Π·Π°Π», ΡΡΠΎ ΠΈΡ
ΠΏΡΠΎΡΠΈΠ²ΠΎΡΠ°ΠΊΠΎΠ²Π°Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΈ ΡΠΈΡΠΎ- ΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠ°Ρ ΡΠ΅Π»Π΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π² ΠΎΡΠ½ΠΎΡΠ΅Π½ΠΈΠΈ ΡΠ°ΠΊΠΎΠ²ΡΡ
ΠΈ Π½ΠΎΡΠΌΠ°Π»ΡΠ½ΡΡ
ΠΊΠ»Π΅ΡΠΎΠΊ Π·Π°Π²ΠΈΡΡΡ ΠΎΡ ΡΡΡΠΎΠ΅Π½ΠΈΡ ΠΈ ΠΊΠΎΠ½ΡΠΈΠ³ΡΡΠ°ΡΠΈΠΈ Π°ΡΠΈΠ»ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΌΠΈΠ½ΠΎ- ΠΈ ΠΏΠΈΡΠΈΠ΄ΠΈΠ»ΠΌΠ΅ΡΠΎΠΊΡΠΈΠΌΠΈΠ½ΠΎΠ³ΡΡΠΏΠΏΡ Π² ΡΠΎΡΡΠ°Π²Π΅ 7-Π°Π»ΠΊΠΈΠ»ΠΈΠ΄Π΅Π½ΠΎΠ²ΠΎΠ³ΠΎ Π·Π°ΠΌΠ΅ΡΡΠΈΡΠ΅Π»Ρ, Π° ΡΠ°ΠΊΠΆΠ΅ ΠΎΡ Π½Π°Π»ΠΈΡΠΈΡ ΠΈΠ»ΠΈ ΠΎΡΡΡΡΡΡΠ²ΠΈΡ N,N-Π΄ΠΈΠΌΠ΅ΡΠΈΠ»Π°ΠΌΠΈΠ½ΠΎΠΌΠ΅ΡΠΈΠ»Π΅Π½ΠΎΠ²ΠΎΠΉ ΠΈ ΠΊΠ°ΡΠ±ΠΎΠΊΡΠΈΠ»ΡΠ½ΠΎΠΉ Π³ΡΡΠΏΠΏ, ΡΠΎΠΎΡΠ²Π΅ΡΡΡΠ²Π΅Π½Π½ΠΎ, Π² ΠΏΠΎΠ»ΠΎΠΆΠ΅Π½ΠΈΡΡ
2 ΠΈ 4 ΡΠ΅ΡΠ΅ΠΌΠΎΠ²ΠΎΠ³ΠΎ ΡΠ΄ΡΠ°
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
Π‘ΠΈΠ½ΡΠ΅Π· ΠΈ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΠ°ΠΊΠΎΠ²ΡΠ΅ ΡΠ²ΠΎΠΉΡΡΠ²Π° ΡΠ»ΠΎΠΆΠ½ΡΡ ΡΡΠΈΡΠΎΠ² 3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-7Ξ±-Ρ Π»ΠΎΡΡΠ΅Ρ-3-Π΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ
Π‘ΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½Ρ ΡΡΠ΅Ρ-Π±ΡΡΠΈΠ»ΠΎΠ²ΡΠ΅ ΡΡΠΈΡΡ 3-Π°Π·ΠΈΠ΄ΠΎΠΌΠ΅ΡΠΈΠ»-, 3-ΠΈΠ·ΠΎΡΠΈΠΎΡΠΈΠ°Π½Π°ΡΠΎΠΌΠ΅ΡΠΈΠ»-, 3-Ρ
Π»ΠΎΡ- ΠΌΠ΅ΡΠΈΠ»- ΠΈ 3-ΠΏΠ°ΡΠ°-Π½ΠΈΡΡΠΎΡΠ΅Π½ΠΈΠ»Π²ΠΈΠ½ΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-7Ξ±-Ρ
Π»ΠΎΡΡΠ΅Ρ-3-Π΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ, Π° ΡΠ°ΠΊΠΆΠ΅ ΡΠ»ΠΎΠΆΠ½ΡΠ΅ ΡΡΠΈΡΡ 3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-7Ξ±-Ρ
Π»ΠΎΡΡΠ΅Ρ-3-Π΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ ΠΈ 2-Π΄ΠΈ-ΠΌΠ΅ΡΠΈΠ»Π°ΠΌΠΈΠ½ΠΎΠΌΠ΅ΡΠΈΠ»Π΅Π½-3-ΠΌΠ΅ΡΠΈΠ»-1,1-Π΄ΠΈΠΎΠΊΡΠΎ-7Ξ±-Ρ
Π»ΠΎΡΡΠ΅Ρ-3-Π΅ΠΌ-4-ΠΊΠ°ΡΠ±ΠΎΠ½ΠΎΠ²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ. ΠΠ±ΠΎΠ±ΡΠ΅Π½Ρ ΠΈ ΠΏΡΠΎΠ°Π½Π°Π»ΠΈΠ·ΠΈΡΠΎΠ²Π°Π½Ρ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΡΠΈΡΠΎΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΠΊΡΠΈΠ½ΠΈΠ½Π³Π° ΡΡΠΈΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ Π² ΠΎΡΠ½ΠΎ- ΡΠ΅Π½ΠΈΠΈ ΡΠ°ΠΊΠΎΠ²ΡΡ
ΠΈ Π½ΠΎΡΠΌΠ°Π»ΡΠ½ΡΡ
ΠΊΠ»Π΅ΡΠΎΠΊ in vitro
3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors
SARS-CoV-2 nsp14 guanine-N7-methyltransferase plays an important role in the viral RNA translation process by catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to viral mRNA cap. We report a structure-guided design and synthesis of 3-(adenosylthio)benzoic acid derivatives as nsp14 methyltransferase inhibitors resulting in compound 5p with subnanomolar inhibitory activity and improved cell membrane permeability in comparison with the parent inhibitor. Compound 5p acts as a bisubstrate inhibitor targeting both SAM and mRNA-binding pockets of nsp14. While the selectivity of 3-(adenosylthio)benzoic acid derivatives against human glycine N-methyltransferase was not improved, the discovery of phenyl-substituted analogs 5p,t may contribute to further development of SARS-CoV-2 nsp14 bisubstrate inhibitors