N-Alkylation and Aminohydroxylation of 2-Azidobenzenesulfonamide gives a Pyrrolobenzothiadiazepine precursor whereas attempted N-Alkylation of 2-Azidobenzamide gives Benzotriazinones and Quinazolinones

N-Alkylation of 2-azidobenzenesulfonamide with 5-bromopent-1-ene gave an N-pentenyl sulfonamide which underwent intramolecular aminohydroxylation to give an N-(2-azidoaryl)sulfonyl prolinol, a precursor for the synthesis of a pyrrolobenzothiadiazepine. The attempted N-alkylation of 2-azidobenzamide gave a separable mixture (~1:1) of a benzotriazinone and a quinazolinone in 72% combined yield. Other primary alkyl halides (3 examples) gave similar mixtures of benzotriazinones and quinazolinones. Benzylic, allylic, secondary and tertiary alkyl halides (5 examples) gave only the benzotriazinones in moderate yields. The results of mechanistic studies show the likely involvement of nitrene intermediates in the quinazolinone pathway and a second pathway involving a DMSO or dimethylsulfide mediated conversion of 2-azidobenzamide into the benzotriazinones

Updating of working memory in ecstasy polydrug users: Findings from fNIRS.

AIMS/OBJECTIVES: Cognitive deficits are now well documented in ecstasy (MDMA) users with type and relative demand of task emerging as important factors. The updating component of executive processes appears to be particularly affected. The study reported here used functional near infrared spectroscopy imaging to investigate changes in cortical haemodynamics during memory updating. METHOD: Twenty ecstasy users and 20 non-users completed verbal and spatial memory updating tasks and brain blood oxygenation and deoxygenation change was measured using functional near infrared spectroscopy. RESULTS: There was no interaction between group and difficulty on the updating tasks, though there was a significant main effect of difficulty on both tasks. The effects of group approached significance on the verbal updating task. There were significant differences in blood oxygenation and deoxygenation change at optodes centred over the right and left dorsolateral prefrontal cortex, with ecstasy users showing greater blood oxygenation than the other groups. DISCUSSION: The lack of a behavioural difference on both tasks but presence of blood oxygenation and deoxygenation changes in letter updating provides support for the notion that ecstasy-polydrug users are investing more effort to achieve the same behavioural output. Total lifetime dose was high, and recency of use was significantly related to most changes, suggesting that heavy and recent use may be particularly detrimental

The genome and transcriptome of Haemonchus contortus, a key model parasite for drug and vaccine discovery

<p>Background: The small ruminant parasite Haemonchus contortus is the most widely used parasitic nematode in drug discovery, vaccine development and anthelmintic resistance research. Its remarkable propensity to develop resistance threatens the viability of the sheep industry in many regions of the world and provides a cautionary example of the effect of mass drug administration to control parasitic nematodes. Its phylogenetic position makes it particularly well placed for comparison with the free-living nematode Caenorhabditis elegans and the most economically important parasites of livestock and humans.</p> <p>Results: Here we report the detailed analysis of a draft genome assembly and extensive transcriptomic dataset for H. contortus. This represents the first genome to be published for a strongylid nematode and the most extensive transcriptomic dataset for any parasitic nematode reported to date. We show a general pattern of conservation of genome structure and gene content between H. contortus and C. elegans, but also a dramatic expansion of important parasite gene families. We identify genes involved in parasite-specific pathways such as blood feeding, neurological function, and drug metabolism. In particular, we describe complete gene repertoires for known drug target families, providing the most comprehensive understanding yet of the action of several important anthelmintics. Also, we identify a set of genes enriched in the parasitic stages of the lifecycle and the parasite gut that provide a rich source of vaccine and drug target candidates.</p> <p>Conclusions: The H. contortus genome and transcriptome provides an essential platform for postgenomic research in this and other important strongylid parasites. </p&gt

Photoredox Catalysts Based on Earth-abundant Metal Complexes

We would like to thank the Engineering and Physical Sciences Research Council and CRITICAT Centre for Doctoral Training for financial support [Ph.D. studentship to B.H.; Grant code: EP/L016419/1]. C.L thanks the Prof. & Mrs Purdie Bequests Scholarship and AstraZeneca for his PhD Studentship.Over the last decade, visible light photoredox catalysis has exploded into the consciousness of the synthetic chemist. The principal photocatalysts used are based on rare and toxic ruthenium(II) and iridium(III) complexes. This critical review focusses on Earth-abundant metal complexes as potential replacement photocatalysts and summarizes the use of photoactive Cu(I), Zn(II), Ni(0), V(V), Zr(IV), W(0), W(VI), Mo(0), Cr(III) , Co(III) and Fe(II) complexes in photoredox reactions. The optoelectronic properties of these complexes and relevant structurally related analogs, not yet used for photoredox catalysis, are disccussed in combination with the reaction scope reported for each photocatalyst. Prospects for the future of photocatalyst design are considered.PostprintPeer reviewe

Axially chiral enamides : substituent effects, rotation barriers, and implications for their cyclization reactions

The barrier to rotation around the N-alkenyl bond of 38 N-alkenyl-N-alkylacetamide derivatives was measured (ΔG⧧ rotation varied between 20 kcal mol–1) were studied to determine the regiochemistry of cyclization. Those with high barriers (>27 kcal mol–1) did not lead to cyclization, but those with lower values produced highly functionalized γ-lactams via a 5-endo-trig radical–polar crossover process that was terminated by reduction, an unusual cyclopropanation sequence, or trapping with H2O, depending upon the reaction conditions. Because elevated temperatures were necessary for cyclization, this precluded study of the asymmetric transfer in the reaction of individual atropisomers. However, enantiomerically enriched atropsiomeric enamides should be regarded as potential asymmetric building blocks for reactions that can be accomplished at room temperature

Ecstasy-related deficits in the updating component of executive processes

Aims Research shows that users of ecstasy (MDMA) exhibit deficits in executive processes. The updating component appears to be particularly susceptible. Less is known about the precise nature of such deficits. The present study sought to determine if ecstasy-related deficits in memory updating are related to serial position of items presented, or length of the list of items. Method Seventy-three ecstasy/polydrug users and seventy-three non-ecstasy users completed tasks of verbal and spatial memory running memory, recalling the most recent items, in lists of varying and unknown length. Participants were categorised according to letter and spatial span (four, five or six), producing six sub-samples for analysis. Results Ecstasy-polydrug users were impaired in four out of the six sub-sample analyses. Three of these were due to impaired recall of earlier serial positions. Conclusions The results of the present study provide further support for updating deficits in ecstasy-polydrug users. The results are suggestive of a breakdown in the maintenance of information in working memory in terms of chunking; it appears that ecstasy/polydrug users are as able as non-ecstasy users to form memory ‘chunks’ from the items, but that such chunks are not retained as effectively