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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 analogs. 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. Parameter 1 Mtb H37Rv MIC90 (µM) 0.30 Mtb MIC90 (µM) (108 strains) 0.60 Intracellular H37Rv MIC80 (µM) 0.25 Antibacterial panel IC50 (µM) ≥16 Mammalian cell (HepG2) Tox50 (µM) 36 clogP 2.99 CLint (mL/min•g) mouse microsomes >30 CLint (mL/min•g) human microsomes 25 Solubility CLND (µM) 266 The compound's intra-macrophage activity, selectivity for mycobacteria vs. other bacterial species, and potency against a broad panel of clinical isolates including MDR and XDR strains, in vitro-cidal behavior and a low frequency of spontaneous resistance 13a suggested a highly promising antitubercular profile. The low microsomal stability was a concern and required improvement. In this paper, we report our efforts to optimize this family of compounds through the synthesis of analogs aimed at retaining the antitubercular potency while improving the overall profile for the series. RESULTS AND DISCUSSION Synthesis and In Vitro Evaluation of Analogs Aiming to explore the chemical space of the series, a library of novel compounds was synthesized and evaluated. The compounds were isolated either as free amines or as salts (hydrochloride or

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