Biocatalytic reduction of nitro-sulfonamides: enzyme engineering, process integration, and sustainable pathways to p-aminobenzenesulfonamide.

Sulfonamides remain important to medicinal and fine-chemical production but conventional aniline precursor routes like Pd-catalysed hydrogenation and Béchamp reductions carry sustainability, safety, and chemoselectivity challenges, especially for N-S bond integrity. This review assesses biocatalytic nitroreduction as a selective alternative for nitro-sulfonamides, focusing on p-aminobenzenesulfonamide (p-ABS). We summarise mechanistic and engineering advances in Type I (oxygen-insensitive) flavin-dependent nitroreductases (NTRs), highlight emerging roles and limits of Old Yellow Enzymes, and discuss auxiliary reductive platforms (H2-driven hydrogenases, photo-/electro-biocatalysis) for improved cofactor economy and endpoint selectivity. Process-intensification strategies, whole-cell vs. cell-free operation, immobilisation, packed-bed flow, on-line LC/IR PAT, and NAD(P)H regeneration via GDH/FDH or electroenzymatic modules are mapped to chemoselectivity risks (hydroxylamine accumulation, azo/azoxy formation) and mass-transfer constraints. We highlight development choices with green metrics (PMI, E-factor) and emphasise early LCA integration to avoid burden shifting from buffer salts or mediator residues. Evidence from continuous NTR reactors and immobilised formats supports scalable, aqueous, low-pressure operation; however, direct data on sulfonamide-linked nitroarenes is limited. This motivates a feasibility screen using an NTR panel (including engineered NfsB lineages), water-rich media with low co-solvent, and O2-tolerant settings. We conclude with a proposed flowsheet for p-ABS coupling immobilised NTR with FDH or electro-NAD(P)H supply, real-time analytics, and membrane-based product extraction. As direct data on sulfonamide-linked nitroarenes remain limited, this roadmap provides a practical and critical starting point for substrate-specific feasibility screening and future development.