a) Primary root scaffold analysis and associated potency distribution for compounds associated with these scaffolds. The clustering was based on the high quality CRCs (classes 1a, 1b or 2a) with maximum inhibition values of >50%. Scaffolds at the bottom of the graph contain as little as five members while scaffolds at the top of the graph contain >1,000 members. b) Root scaffolds composed of heterocycles associated with >200 compounds. Representative scaffolds are shown, the most prominent of which were the thiazole (i), pyridine (ii, found in quinolines), and imidazole (iii) ring structures. A series of oxadiazoles (xiii) were also prevalent. Also shown here are (iv) pyrazole, (v) furan, (vi) pyrrole, (vii) thiophene, (viii) pyrimidine, (ix) dihydro-dioxine, (x) dioxole, (xi) isooxazole, (xii) oxazole, (xiv) thiadiazole. c) Potency distribution for the scaffolds i – iii, which were highly populated in the dataset. Scaffold levels are shown to the left of the potency heat map and are depicted as colored dots, with increasing structural complexity proceeding from left to right (i.e., orange indicating the least complex scaffold level and red the highest complexity shown here). Potency values are in μM and the compounds are colored based on the scaffold level which includes the substructure. Of note, not every compound in the potency distribution analysis achieved the highest level of structural complexity, as seen with compounds (5) and (6). An example of both a potent and a weakly active compound is shown for benzothiazoles (1, 2), quinolines (3, 4), pyridines (5, 6), benzimidazoles (7, 8), as well as benzimidazoles fused to other ring systems (9, 10). It was found that generally flat, planar structures were more potent FLuc inhibitors compared to more complex, branched or highly angular structures. Alternate analysis and support for this data is shown in .