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. 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

Синтез и цитотоксическая активность производных трет-бутилового эфира 7Z-ацетилметилен-3-метил-3-цефем-4-карбоновой кислоты

Конденсацией ацетилметиленовой группы в трет-бутиловом эфире 7Z-аце- тилметилен-3-метил-3-цефем-4-карбоновой и 7Z-ацетилметилен-3-метил-1,1-ди- оксо-3-цефем-4-карбоновой кислот и в 7Z-ацетилметилен-3-метил-1,1-диоксо- 3-цефеме с арилметоксиаминами и О-алкилированием трет-бутилового эфира 7Z-(2-гидроксимино)пропилиден-3-метил-1,1-диоксо-3-цефем-4-карбоновой киc- лоты замещенными бензилбромидами, а также пиридилметилхлоридами синте- зированы арилметоксимино- и пиридилметоксиминопроизводные этих соединений в син- и анти-изомерной форме. С помощью реагента Вильсмайера введена N,N-диметиламинометиленовая группа в положение 2 цефемового ядра трет-бутиловых эфиров 7Z-[2-(арил- метоксимино)пропилиден]-3-метил-1,1-диоксо-3-цефем-4-карбоновой кислоты. После- дующая трансформация N,N-диметиламинометилензамещенных цефемов гид- роксиламином привела к получению 3Z-[2-(анти-арилметоксимино)пропилиден]-трет-бутоксикарбонилметил-4-(5-метил-4-изоксазолилсульфонил)азетидин-2-онов. Конденсацией ацетильной группы в трет-бутиловом эфире 7Z-ацетил- метилен-3-метил-1,1-диоксо-3-цефем-4-карбоновой кислоты с 4-бромфенил- гидразином синтезирован цефем с 2-(4-бромфенилгидразоно)пропилиденовой группой в положении 7. Ацилированием трет-бутилового эфира 7Z-(2-гидрокс- имино)пропилиден-3-метил-1,1-диоксо-3-цефем-4-карбоновой киcлоты хлорангид- ридом 2-бромбензойной кислоты синтезирован цефем с 2-(2-бромбензоилокс- имино)пропилиденовой группой в положении 7. Биологический скрининг синтезированных соединений в отношении раковых и нормальных клеток in vitro показал, что их противораковая активность и цито- токсическая селективность в отношении раковых и нормальных клеток зависят от строения и конфигурации арилметоксимино- и пиридилметоксиминогруппы в составе 7-алкилиденового заместителя, а также от наличия или отсутствия N,N-диметиламинометиленовой и карбоксильной групп, соответственно, в положениях 2 и 4 цефемового ядра

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

Синтез и противораковые свойства сложных эфиров 3-метил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты

Синтезированы трет-бутиловые эфиры 3-азидометил-, 3-изотиоцианатометил-, 3-хлор- метил- и 3-пара-нитрофенилвинил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты, а также сложные эфиры 3-метил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты и 2-ди-метиламинометилен-3-метил-1,1-диоксо-7α-хлорцеф-3-ем-4-карбоновой кислоты. Обобщены и проанализированы результаты цитотоксического скрининга этих соединений в отно- шении раковых и нормальных клеток 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