Diversification and Development of Spiros Compounds for the Treatment of Tuberculosis
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Osende, Javier GonzálezAbstract
This thesis reports the synthesis and biological evaluation of novel molecules intended for the treatment of tuberculosis. Tuberculosis is a dangerous infectious disease caused by the bacterium Mycobacterium tuberculosis, which if not treated or treated inefficiently can be fatal. ...
See moreThis thesis reports the synthesis and biological evaluation of novel molecules intended for the treatment of tuberculosis. Tuberculosis is a dangerous infectious disease caused by the bacterium Mycobacterium tuberculosis, which if not treated or treated inefficiently can be fatal. It was estimated that in 2012 tuberculosis was responsible for the death of 1.3 million people and the infection of 8.6 million more. The current treatment for tuberculosis consists of a combination of drugs, which typically involve excessively long term treatments, resulting in many cases in the partial completion of the treatment. In recent years multi– and extensively drug resistant strains have evolved. New drugs with new mechanisms of action are urgently needed. The anti–tubercular drug pipeline is weak, with few new chemical entities currently in clinical trials. In an attempt to fulfil this need, GlaxoSmithKline recently reported several new chemical series with potential for the treatment of TB. One, based on a thiophene spirocycle core, and named the Spiros family, was found to inhibit the growth of Mycobacterium tuberculosis through a different mechanism of action from any other approved anti–tubercular drug. A synthesis of this Spiros family has recently been developed via a three-steps oxa–Pictet–Spengler reaction, and several members of this family have exhibited potency vs. virulent strains of TB. This thesis reports the synthesis of several novel compounds with variation in the heterocyclic ring of the Spiros family, a portion of the molecule that has not been explored to date. The oxa–Pictet–Spengler reaction was used as the key transformation of this reaction, tolerating a range of aromatic heterocycles. Initial biological activity data for the compounds synthesised were obtained, indicating promising levels of potency comparable with already-reported analogs in this series vs. the virulent strain of TB. It was found that potent anti-TB molecules are available in one chemical step from commercial materials.
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See moreThis thesis reports the synthesis and biological evaluation of novel molecules intended for the treatment of tuberculosis. Tuberculosis is a dangerous infectious disease caused by the bacterium Mycobacterium tuberculosis, which if not treated or treated inefficiently can be fatal. It was estimated that in 2012 tuberculosis was responsible for the death of 1.3 million people and the infection of 8.6 million more. The current treatment for tuberculosis consists of a combination of drugs, which typically involve excessively long term treatments, resulting in many cases in the partial completion of the treatment. In recent years multi– and extensively drug resistant strains have evolved. New drugs with new mechanisms of action are urgently needed. The anti–tubercular drug pipeline is weak, with few new chemical entities currently in clinical trials. In an attempt to fulfil this need, GlaxoSmithKline recently reported several new chemical series with potential for the treatment of TB. One, based on a thiophene spirocycle core, and named the Spiros family, was found to inhibit the growth of Mycobacterium tuberculosis through a different mechanism of action from any other approved anti–tubercular drug. A synthesis of this Spiros family has recently been developed via a three-steps oxa–Pictet–Spengler reaction, and several members of this family have exhibited potency vs. virulent strains of TB. This thesis reports the synthesis of several novel compounds with variation in the heterocyclic ring of the Spiros family, a portion of the molecule that has not been explored to date. The oxa–Pictet–Spengler reaction was used as the key transformation of this reaction, tolerating a range of aromatic heterocycles. Initial biological activity data for the compounds synthesised were obtained, indicating promising levels of potency comparable with already-reported analogs in this series vs. the virulent strain of TB. It was found that potent anti-TB molecules are available in one chemical step from commercial materials.
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Date
2018-06-12Licence
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