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Efficient Synthesis and Anti-Tubercular Activity of a Series of Spirocycles: An Exercise in Open Science.

Badiola KA, Quan DH, Triccas JA, Todd MH - PLoS ONE (2014)

Bottom Line: GlaxoSmithKline recently placed the structures and activities of 177 novel anti-tubercular leads in the public domain, as well as the results of ongoing optimisation of some of the series.The new compounds are attractive from a medicinal chemistry standpoint and some were potent against the virulent strain, suggesting this class is worthy of further study.The research was carried out using open source methodology, providing the community with full access to all raw experimental data in real time.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, The University of Sydney, New South Wales, Australia.

ABSTRACT
Tuberculosis afflicts an estimated 2 billion people worldwide and causes 1.3 million deaths annually. Chemotherapeutic solutions rely on drugs developed many years ago, with only one new therapeutic having been approved in the last 40 years. Given the rise of drug-resistant strains, there is an urgent need for the development of a more robust drug development pipeline. GlaxoSmithKline recently placed the structures and activities of 177 novel anti-tubercular leads in the public domain, as well as the results of ongoing optimisation of some of the series. Since many of the compounds arose from screening campaigns, their provenance was unclear and synthetic routes were in many cases not reported. Here we present the efficient synthesis of several novel analogues of one family of the GSK compounds-termed "Spiros"-using an oxa-Pictet-Spengler reaction. The new compounds are attractive from a medicinal chemistry standpoint and some were potent against the virulent strain, suggesting this class is worthy of further study. The research was carried out using open source methodology, providing the community with full access to all raw experimental data in real time.

No MeSH data available.


Related in: MedlinePlus

Re-evaluating the route to the 2° amine core 3 (blue).(A) The attempted route based on the patent literature procedure [12]. The dotted lines represent the additional step (red) required to attempt cyclisation strictly under the patent conditions. (B) The revised strategy: cyclise to give 6 followed by debenzylation to give the 2° amine 3 (blue).
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pone-0111782-g004: Re-evaluating the route to the 2° amine core 3 (blue).(A) The attempted route based on the patent literature procedure [12]. The dotted lines represent the additional step (red) required to attempt cyclisation strictly under the patent conditions. (B) The revised strategy: cyclise to give 6 followed by debenzylation to give the 2° amine 3 (blue).

Mentions: The ketal 2 may therefore be crucial in this transformation where precise tuning of reactivity and conditions is necessary to promote conversion but not decomposition. However, formation of this ketal would unfavourably introduce another step in the synthesis (A, red, Figure 4). We therefore devised an alternate strategy for accessing the secondary amine 3: carrying out the oxa-Pictet–Spengler reaction using 4 prior to removal of the N-benzyl group (B).


Efficient Synthesis and Anti-Tubercular Activity of a Series of Spirocycles: An Exercise in Open Science.

Badiola KA, Quan DH, Triccas JA, Todd MH - PLoS ONE (2014)

Re-evaluating the route to the 2° amine core 3 (blue).(A) The attempted route based on the patent literature procedure [12]. The dotted lines represent the additional step (red) required to attempt cyclisation strictly under the patent conditions. (B) The revised strategy: cyclise to give 6 followed by debenzylation to give the 2° amine 3 (blue).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262224&req=5

pone-0111782-g004: Re-evaluating the route to the 2° amine core 3 (blue).(A) The attempted route based on the patent literature procedure [12]. The dotted lines represent the additional step (red) required to attempt cyclisation strictly under the patent conditions. (B) The revised strategy: cyclise to give 6 followed by debenzylation to give the 2° amine 3 (blue).
Mentions: The ketal 2 may therefore be crucial in this transformation where precise tuning of reactivity and conditions is necessary to promote conversion but not decomposition. However, formation of this ketal would unfavourably introduce another step in the synthesis (A, red, Figure 4). We therefore devised an alternate strategy for accessing the secondary amine 3: carrying out the oxa-Pictet–Spengler reaction using 4 prior to removal of the N-benzyl group (B).

Bottom Line: GlaxoSmithKline recently placed the structures and activities of 177 novel anti-tubercular leads in the public domain, as well as the results of ongoing optimisation of some of the series.The new compounds are attractive from a medicinal chemistry standpoint and some were potent against the virulent strain, suggesting this class is worthy of further study.The research was carried out using open source methodology, providing the community with full access to all raw experimental data in real time.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, The University of Sydney, New South Wales, Australia.

ABSTRACT
Tuberculosis afflicts an estimated 2 billion people worldwide and causes 1.3 million deaths annually. Chemotherapeutic solutions rely on drugs developed many years ago, with only one new therapeutic having been approved in the last 40 years. Given the rise of drug-resistant strains, there is an urgent need for the development of a more robust drug development pipeline. GlaxoSmithKline recently placed the structures and activities of 177 novel anti-tubercular leads in the public domain, as well as the results of ongoing optimisation of some of the series. Since many of the compounds arose from screening campaigns, their provenance was unclear and synthetic routes were in many cases not reported. Here we present the efficient synthesis of several novel analogues of one family of the GSK compounds-termed "Spiros"-using an oxa-Pictet-Spengler reaction. The new compounds are attractive from a medicinal chemistry standpoint and some were potent against the virulent strain, suggesting this class is worthy of further study. The research was carried out using open source methodology, providing the community with full access to all raw experimental data in real time.

No MeSH data available.


Related in: MedlinePlus