Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis


Journal of Medicinal Chemistry


Ana Guardia, Jessica Baiget, Mónica Cacho, Arancha Pérez, Montserrat Ortega-Guerra, Winston Nxumalo, Setshaba D. Khanye, Joaquín Rullas, Fátima Ortega, Elena Jiménez, Esther Pérez-Herrán, María Teresa Fraile-Gabaldón, Jorge Esquivias, Raquel Fernández, Esther Porras-De Francisco, Lourdes Encinas, Marta Alonso, Ilaria Giordano, Cristina Rivero, Juan Miguel-Siles, Javier G. Osende, Katrina A. Badiola, Peter J. Rutledge , Matthew H. Todd, Modesto Remuiñán, and Carlos Alemparte



Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.

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