We then turned our attention to the N-benzyl moiety in the southern region of YC-1 (Table ). Removing the N-substituent entirely (compound 18) or replacing with a small aliphatic group such as methyl (compound 19) or isoprenyl (20) led to partial inhibition. Completely removing the spacer (22) or increasing the spacer length to two carbons (23) led to reduced potency, indicating the preference of a one-carbon spacer in the benzyl group of YC-1. Similarly, the nature of the spacer appeared to be important as replacing the methylene linker with a carbonyl (24), sulfone (25), or carbamate (26) resulted in inferior activity. A small hydrophobic methyl group added to the methylene spacer (27) registered an IC50 of ~4 M. The SAR in Table emphasized that the optimal spacer in the southern region was the one-carbon methylene group seen in YC-1. Retaining the optimal one-carbon spacer, we embarked on the SAR exploration of the southern phenyl ring itself (Table ). The addition of small substituents including fluorine (compounds 28-30), chlorine (compounds 31-33), methyl (compounds 34-36), and methoxy groups (37-39) at the ortho, meta, or para positions of the phenyl ring was tolerated. Notably the ortho-and meta-OMe groups in analogs 37 and 38 offered slightly better potencies than YC-1. Similarly, introducing 2pyridine (40), 3-pyridine (41), or 4-pyridine (42) in place of the benzyl group also led to improved potencies. However, incorporating more heteroatoms as in pyrimidine 43 and thiazole 44 failed to bring additional benefits. Combining the two beneficial elements, a ring nitrogen and a methoxy substituent, provided compounds 45-47 with analog 45 registering a benchmark IC50 of 0.21 M.