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

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.

Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth

“…Synthesis of related spirocyclic amines has been previously reported. 19 , 39 The general synthetic routes employed for the synthesis of pyrazole containing spirocyclic amines are shown below ( Scheme 1 ). The appropriately substituted R1 aryls or heteroaryls were reacted with 1-[(4-methoxyphenyl)methyl]piperidin-4-one to form 48 , which was then deprotected to form amine 49 .…”

Experiences with a researcher-centric ELN

“…The snapshot is stored in an institutional repository and can be downloaded subsequently. 21 LabTrove is also used at the Science & Technology Facilities Council (STFC) Central Laser Facility (CLF) at the Rutherford Appleton Laboratory (RAL) by staff and users of the Artemis facility. The ISIS group at STFC uses the ELN to enable scientists to keep track of experiment status and the data reduction workow for a live experiment.…”

The Evolution of Digital Chemistry at Southampton

“…The resultingL abTrove software [14] has now been usedb ys everal research groups, [44] of which we would highlightt he open notebook sciencec onsortia run by Mat To dd. [45,46] …”