Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.
The in situ-generation of sulfur ylides by the gold-catalysed rearrangement of propargylic carboxylates in the presence of sulfides has resulted in highly efficient and novel transformations.The transition-metal-catalysed decomposition of diazo compounds is a well-established and powerful strategy to access metal carbenoids, which may then be used to generate reactive intermediates. A powerful example is the Doyle-Kirmse reaction, which generates new C-C and C-S bonds (Scheme 1), most notably under Rh(II) and Cu(I) catalysis. 1 In this process, an allyl sulfide 3 reacts with carbenoid 2 to give a sulfur ylide intermediate 4 that is capable of undergoing a [2,3]-sigmatropic rearrangement. 2 This overall strategy, however, is limited: first, by safety concerns associated with the handling and use of diazo compounds; second, by the synthetic impact associated with the introduction of a diazo functionality. With these factors in mind, we recently initiated a programme to explore the utility of reactive intermediates derived from metal carbenoids that are accessed via rearrangement processes. By bypassing the preparation and use of diazo compounds, this strategy should result in increased overall synthetic efficiency, whilst also decreasing potential operating risks.As a starting point, we studied the reaction between a propargylic carboxylate and an allyl sulfide (Scheme 2). Within the rapidly developing area of gold-and platinum-based homogeneous catalysis, 3,4 the propargylic carboxylate moiety has invited special interest owing to its propensity to act as an a-diazocarbonyl surrogate upon rearrangement to metal carbenoid 7. 5 This reactivity has been successfully employed in a number of transformations, in particular through reaction with additional C-C p-systems. 6,7 We questioned whether this mode of reactivity could therefore be used as an alternative strategy to access reactive intermediates, such as sulfur ylides. If successful, the combination of ylide
The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani , the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 ( 1 ) for VL.
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