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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

Executing the revised strategy towards the synthesis of spirocycle core as the 2° amine 3.(A) The acid-mediated cyclisation. (B) Attempts to synthesise the 2° amine using catalytic hydrogenolysis. (C) 1-chloroethyl chloroformate was effective at producing the secondary amine 3. (D) 2-chloroethyl chloroformate resulted in incomplete deprotection of 6.
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pone-0111782-g005: Executing the revised strategy towards the synthesis of spirocycle core as the 2° amine 3.(A) The acid-mediated cyclisation. (B) Attempts to synthesise the 2° amine using catalytic hydrogenolysis. (C) 1-chloroethyl chloroformate was effective at producing the secondary amine 3. (D) 2-chloroethyl chloroformate resulted in incomplete deprotection of 6.

Mentions: The first step of the revised strategy proved effective; the N-benzylated core (6) was obtained in consistently good yield over a number of repeats (A, Figure 5). The reaction was promoted by 1.5 equivalents of methanesulfonic acid instead of triflic acid, the former being easier to handle. To counter the reduced acidity, the reaction temperature was increased. Lowering the acid loading or reaction time gave a mixture of the product 6 and starting material; the ketone 4 was inseparable from the product 6 in the post-reaction workup or by flash chromatography. The methanesulfonic acid-mediated reaction initially carried out was the most effective at cleanly obtaining the desired spirocycle 6.


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)

Executing the revised strategy towards the synthesis of spirocycle core as the 2° amine 3.(A) The acid-mediated cyclisation. (B) Attempts to synthesise the 2° amine using catalytic hydrogenolysis. (C) 1-chloroethyl chloroformate was effective at producing the secondary amine 3. (D) 2-chloroethyl chloroformate resulted in incomplete deprotection of 6.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111782-g005: Executing the revised strategy towards the synthesis of spirocycle core as the 2° amine 3.(A) The acid-mediated cyclisation. (B) Attempts to synthesise the 2° amine using catalytic hydrogenolysis. (C) 1-chloroethyl chloroformate was effective at producing the secondary amine 3. (D) 2-chloroethyl chloroformate resulted in incomplete deprotection of 6.
Mentions: The first step of the revised strategy proved effective; the N-benzylated core (6) was obtained in consistently good yield over a number of repeats (A, Figure 5). The reaction was promoted by 1.5 equivalents of methanesulfonic acid instead of triflic acid, the former being easier to handle. To counter the reduced acidity, the reaction temperature was increased. Lowering the acid loading or reaction time gave a mixture of the product 6 and starting material; the ketone 4 was inseparable from the product 6 in the post-reaction workup or by flash chromatography. The methanesulfonic acid-mediated reaction initially carried out was the most effective at cleanly obtaining the desired spirocycle 6.

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