Activity of 6-aryl-pyrrolo[2,3-d]pyrimidine-4-amines to Tetrahymena

A series 6-aryl-pyrrolo[2,3-d]pyrimidine-4-amines (43 compounds), some of which are epidermal growth 22 factor tyrosine kinase inhibitors, were tested for their protozoal toxicity using an environmental Tetrahy- 23 mena strain as model organism. The protozoacidal activity of the analogues was found to be highly 24 dependent on a 4-hydroxyl group at the 6-aryl ring, and a chiral 1-phenylethanamine substituent in posi- 25 tion 4. Further, the potency was affected by the aromatic substitution pattern of the phenylethanamine: 26 the unsubstituted, the meta-fluoro and the para-bromo substituted derivatives had the lowest minimum 27 protozoacidal concentrations (8–16 lg/mL). Surprisingly, both enantiomers were found to have high 28 potency suggesting that this compound class could have several modes of action. No correlation was 29 found between the compounds protozoacidal activity and the in vitro epidermal growth factor receptor 30 tyrosine kinase inhibitory potency. This suggests that the observed antimicrobial effects are related to 31 other targets. Testing towards a panel of kinases indicated several alternative modes of actio

A highly selective purine-based inhibitor of CSF1R potently inhibits osteoclast differentiation

The colony-stimulating factor 1 receptor (CSF1R) plays an important role in the regulation of many inflammatory processes, and overexpression of the kinase is implicated in several disease states. Identifying selective, smallmolecule inhibitors of CSF1R may be a crucial step toward treating these disorders. Through modelling, synthesis, and a systematic structure-activity relationship study, we have identified a number of potent and highly selective purine-based inhibitors of CSF1R. The optimized 6,8-disubstituted antagonist, compound 9, has enzymatic IC50 of 0.2 nM, and displays a strong affinity toward the autoinhibited form of CSF1R, contrasting that of other previously reported inhibitors. As a result of its binding mode, the inhibitor shows excellent selectivity (Selectivity score: 0.06), evidenced by profiling towards a panel of 468 kinases. In cell-based assays, this inhibitor shows dose-dependent blockade of CSF1-mediated downstream signalling in murine bone marrow-derived macrophages (IC50 = 106 nM) as well as disruption of osteoclast differentiation at nanomolar levels. In vivo experiments, however, indicate that improve metabolic stability is needed in order to further progress this compound class

Activation of multiple stress responses in Staphylococcus aureus substantially lowers the minimal inhibitory concentration when combining two novel antibiotic drug candidates

The past few decades have been plagued by an increasing number of infections caused by antibiotic resistant bacteria. To mitigate the rise in untreatable infections, we need new antibiotics with novel targets and drug combinations that reduce resistance development. The novel β-clamp targeting antimicrobial peptide BTP-001 was recently shown to have a strong additive effect in combination with the halogenated pyrrolopyrimidine JK-274. In this study, the molecular basis for this effect was examined by a comprehensive proteomic and metabolomic study of the individual and combined effects on Staphylococcus aureus. We found that JK-274 reduced activation of several TCA cycle enzymes, likely via increasing the cellular nitric oxide stress, and BTP-001 induced oxidative stress in addition to inhibiting replication, translation, and DNA repair processes. Analysis indicated that several proteins linked to stress were only activated in the combination and not in the single treatments. These results suggest that the strong additive effect is due to the activation of multiple stress responses that can only be triggered by the combined effect of the individual mechanisms. Importantly, the combination dose required to eradicate S. aureus was well tolerated and did not affect cell viability of immortalized human keratinocyte cells, suggesting a species-specific response. Our findings demonstrate the potential of JK-274 and BTP-001 as antibiotic drug candidates and warrant further studies

Vellykket Organisk Kjemisk Vintermøte 2020

Organisk Kjemiske Vintermøte (OKV35) ble arrangert 9.-12. januar, og samlet 130 deltakere fra de norske universitetene og industri med tiknytning til feltet. Møtet viser at organisk kjemi på tross av en utfordrende finansieringssituasjon er et felt i stadig utvikling

Acetonitrile as a Building Block and Reactant

Acetonitrile is popular as a solvent for performing organic reactions, as a ligand in inorganic chemistry, as a mobile phase in chromatography, and as an electrolyte solvent in dye-sensitized solar cells. This is mainly due to its ability to dissolve both polar and nonpolar components. However, acetonitrile is also a valuable building block allowing atom-efficient transformations in synthetic organic chemistry. The aim of this review is to highlight synthetic transformations using acetonitrile, covering both classical approaches and modern strategies proceeding through radical intermediates or mediated by metal catalysis. Besides showcasing synthetic protocols useful for acetonitrile and analogues, warnings for when not to use acetonitrile as a solvent are also provided

Is literature data useful for identifying enzyme catalysts for new substrates? A case study on reduction of 1-aryl-2-alkanoates

The use of literature data to identify catalysts for a novel transformation is a commonly used approach. Herein, we have evaluated if this is a viable strategy in enzyme catalysis, using asymmetric reduction of 1-aryl-2-alkanoates as a model system. The study, which includes data from 24 ketone substrates and 108 enzymes, clearly identifies pitfalls with this approach, but anyhow shows that literature data is highly useful for identification of enantioselective catalysts. By combining data for selectivity and rate useful catalyst for converting different substrates to their corresponding (R)- and (S)-enantiomers are highlighted

Directed Lithiation of Protected 4-Chloropyrrolopyrimidine: Addition to Aldehydes and Ketones Aided by Bis(2-dimethylaminoethyl)ether

Pyrrolopyrimidines are important scaffolds for the preparation of bioactive molecules. Therefore, developing efficient and flexible ways for selective functionalization of the pyrrolopyrimidine skeleton is of interest. We have investigated lithiation-addition at C-6 of protected 4-chloro-7H-pyrrolo [2,3-d]pyrimidine as a route to new building blocks for medicinal chemistry. It was found that bis(2-dimethylaminoethyl) ether as an additive increased the yield in the additional reaction with benzaldehyde. Deuterium oxide quench experiments showed that this additive offered both a higher degree of lithiation and increased stability of the lithiated intermediate. The substrate scope of the protocol was investigated with 16 aldehydes and ketones, revealing the method to be excellently suited for reaction with aldehydes, cyclohexanone derivatives and 2,2,2-trifluoroacetophenone, while being less efficient for acetophenones. Yields in the range of 46–93% were obtained

Directed Lithiation of Protected 4-Chloropyrrolopyrimidine: Addition to Aldehydes and Ketones Aided by Bis(2-dimethylaminoethyl)ether

Pyrrolopyrimidines are important scaffolds for the preparation of bioactive molecules. Therefore, developing efficient and flexible ways for selective functionalization of the pyrrolopyrimidine skeleton is of interest. We have investigated lithiation-addition at C-6 of protected 4-chloro-7H-pyrrolo [2,3-d]pyrimidine as a route to new building blocks for medicinal chemistry. It was found that bis(2-dimethylaminoethyl) ether as an additive increased the yield in the additional reaction with benzaldehyde. Deuterium oxide quench experiments showed that this additive offered both a higher degree of lithiation and increased stability of the lithiated intermediate. The substrate scope of the protocol was investigated with 16 aldehydes and ketones, revealing the method to be excellently suited for reaction with aldehydes, cyclohexanone derivatives and 2,2,2-trifluoroacetophenone, while being less efficient for acetophenones. Yields in the range of 46–93% were obtained

Effect of Auxiliary Donors on 3,8-Phenothiazine Dyes for Dye-Sensitized Solar Cells

Phenothiazines are one of the more common dye scaffolds for dye-sensitized solar cells. However, these sensitizers are exclusively based on a 3,7-substitution pattern. Herein, we have synthesized and characterized novel 3,8-substituted phenothiazine dyes in order to evaluate the effect of auxiliary donor groups on the performance of this new dye class. The power conversion efficiency increased by 7%–10% upon insertion of an auxiliary donor in position 8 of the phenothiazine, but the structure of the auxiliary donor (phenyl, naphthyl, pyrene) had a low impact when electrodes were stained with chenodeoxycholic acid (CDCA) additive. In the absence of CDCA, the highest power conversion efficiency was seen for the phenyl-based sensitizer attributed to a higher quality dye-monolayer. By comparing the novel dyes to their previously reported 3,7- analogues, only subtle differences were seen in photophysical, electrochemical, and performance measurements. The most notable difference between the two geometries is a lowering of the oxidation potentials of the 3,8-dyes by 40–50 mV compared to the 3,7-analogues. The best auxiliary donor for the 3,8-phenothiazine dyes was found to be pyrenyl, with the best device delivering a power conversion efficiency of 6.23% (99 mW cm−2, 10 eq. CDCA, JSC = 10.20 mA cm−2, VOC = 791 mV, and FF = 0.765)

A comprehensive experimental study of five fundamental phenothiazine geometries increasing the diversity of the phenothiazine dye class for dye-sensitized solar cells

Phenothiazine is a versatile scaffold frequently used in both pharmaceutical and photovoltaic applications. Still, the structural diversity within the class of phenothiazine sensitizers for dye-sensitized solar cells is minute. Substituents are found in 3, 7 and 10-positions, often all three. In this work, we report the synthesis and evaluation of sensitizers illuminating five geometries for the phenothiazine dye class, of which three are novel geometries. Eleven sensitizers were prepared, investigating auxiliary donor contributions, effect of π-spacer and also the position of the anchoring group. We have established that the π-spacer has to be connected para to the 10H nitrogen atom of phenothiazine, the 3-position. Also, thiophene is a far superior π-spacer than phenyl, but we were unable to find any significant photovoltaic performance differences between the 3,7 and 3,8 geometries. A higher dye loading for the 3,8 geometry indicates there is hidden potential in this geometry which could be harvested by further optimization. The best device of the study was fabricated with AFB-27 of the 3,8 geometry delivering a PCE of 5.88% (JSC = 10.28 mA cm−2, VOC = 773 mV, FF = 0.75) under 1 sun AM 1.5G illumination