We began our SAR investigations by preparing a wide variety of analogues with variation in the northwest aryl substituent; the aim was to capitalize on the potency of the benzothiophene of 822 while reducing the potential metabolic liabilities of that motif. As shown in Figure , several fused bicycles were tolerated; of note is the "reverse" (6-substituted) thiophene 830 that was found to be almost equipotent to the original compound 822 (unlike the less potent 3-substituted analogue 832) and the benzofuran pair 821 and 829 that were similarly potent. Compounds with bicyclic motifs containing unsaturated rings were found to be ineffective (e.g., 827/828), as were aromatic nitrogen-containing fused bicycles (e.g., benzothiazoles 835 and 836, quinoline 833). Figure . Heat map of in vitro potency against MRSA of analogues with variations in the northwest and southwest substituents. Color gradient: green < 4 μg/mL; yellow < 16 μg/mL; red = 32 μg/mL. We additionally explored a variety of simpler, substituted phenyl rings at the northwest position. Replacement of the benzofuran moiety in 821 with para-tolyl (865, green region) maintained potency; other para-substituted phenyl rings (e.g., in 824, 875, and 975) resulted in significantly improved activity against MRSA when compared to the analogue with an unsubstituted phenyl ring (870). Small alterations to the para-substituent significantly influenced potency (e.g., 824 vs. 838), though a group in this position generally performed better than the same group in the meta position (e.g., 865 vs. 976, 975 vs. 864). A focused library based on the promising compound 975 was synthesized and evaluated (Table , Supplementary Information -Biology) but none of the compounds retained the potency of the parent. More oxidized substituents, such as acyl (973), methyl sulfone (837), or dimethylamide (974), were not tolerated (Figure , red region).