Table 4. Rationally designed derivatives (D1–D5) of the four lead resin acids—callitrisic, levopimaric, palustric and pimaric acids. For each analog, the parent scaffold, point of modification, appended functional group, and intended purpose (e.g., classical CA zinc-binding headgroup, solubility enhancement, or conjugation handle) are listed. Designs were positioned on solvent-exposed regions indicated by our binding model to preserve the hydrophobic core contacts. Abbreviations: CA, carbonic anhydrase; SA, sulfonamide; UR, ureido; PEG₂–OH, 2-carbon polyethylene glycol alcohol; Az, azide “click” handle; p-FBnAm, para-fluorobenzyl amide.

ID	Parent acid	Modification site	New group
D1	Callitrisic	–COOH → –CONH–SO2NH2 (primary sulfonamide)	Classic CA zinc-binding head; boosts potency/selectivity
D2	Callitrisic	–COOH → ureido (–CONH–NH–CO–NH2)	Alternative CA-binding motif; H-bonding network
D3	Levopimaric	–COOH esterified with –O–(CH2)2–OH	Raise solubility; potential prodrug; keeps hydrophobic core
D4	Palustric	Side-chain alkene click-handle –CONH–(CH2)3–N3	Enables conjugation/imaging (CuAAC)
D5	Pimaric	–COOH → para-fluorobenzyl amide	Adds π–π stacking, tweaks electronics, improves stability