Metabolism is primarily via phase II glucuronidation of the phenolic OH; no major oxidative metabolites detected. | Modification | Effect on DHPS IC₅₀ | Comment | |--------------|----------------------|---------| | Methoxy → OH (para) | ↑ 5‑fold (0.2 nM → 1 nM) | Loss of electron‑donating effect reduces binding. | | Pyridyl → 3‑pyridyl | No change | Position of nitrogen tolerates shift. | | Benzylic OH → OMe | ↑ 10‑fold (0.42 nM → 4 nM) | Hydrogen‑bond donor crucial for pocket interaction. | | Amide → N‑methyl amide | ↑ 2‑fold (0.42 nM → 0.8 nM) | Slight steric hindrance. | | Addition of 2‑fluoro on phenyl | ↓ 3‑fold (0.42 nM → 0.14 nM) | Improves lipophilicity and pocket fit. |