(1) and R3 hydrogen (a) with a highly electron-withdrawing R1 substituent (R1sub-VI). We wanted to design this NCB to look more similar to current structures to ensure the calculated properties are reasonable because the majority of structures in literature include 1 as the R2 substituent and a and the R3 substituent. In addition to altering the R1 substituent, we also looked at how changing the R2 and R3 substituents impacted stability. To do this, we designed four structures with new R2 substituents. These moieties included a thioaldehyde (R2sub-I), thioketone (R2sub-II), trifluoromethyl (R2sub-III), and nitro (R2sub-IV). Thioamides have literature precedent as dinucleotide biomimetic cofactors, which share most of their structure with NAD(P)H, and are proposed to behave similarly to their amide counterparts but have higher reduction potentials than the natural cofactors. We selected a thioketone rather than a thioamide because ketones demonstrate higher stability than amides in our library. Additionally, the increased stabilities shown by R2 aldehydes led us to also choose a thioaldehyde due to the increased stability shown by aldehydes in our study. Electron-withdrawing groups seem to improve stability at the R2 position, with aldehydes performing so well, so we selected a highly electron-withdrawing substituent, trifluoromethyl, to further investigate this trend. This reasoning also led us to design an NCB with a nitro R2 substituent. Additionally, we designed two structures with a trifluoromethyl R3 substituent (R3sub-I & R3sub-II). We selected this moiety as a possible R3 substituent to test if electron-withdrawing effects at this position would have any influence on stability in addition to the bulkiness of the substituent. Trifluoromethyl substituents have only a slightly larger size than the previously tested methyl substituent but are more electron-withdrawing.