N-Cycloamino substituent effects on the packing architecture of ortho-sulfanilamide molecular crystals and their in silico carbonic anhydrase II and IX inhibitory activities

Abstract

In the search for new `sulfa drugs' with therapeutic properties, o-nitrosulfonamides and N-cycloamino-o-sulfanilamides were synthesized and characterized using techniques including ¹H NMR, ¹³C NMR and FT-IR spectroscopy, and single-crystal X-ray diffraction (SC-XRD). The calculated density functional theory (DFT)-optimized geometry of the molecules showed similar conformations to those obtained by SC-XRD. Molecular docking of N-piperidinyl-o-sulfanilamide and N-indolinyl-o-sulfanilamide supports the notion that o-sulfanilamides are able to bind to human carbonic anhydrase II and IX inhibitors (hCA II and IX; PDB entries 4iwz and 5fl4). Hirshfeld surface analyses and DFT studies of three o-nitrosulfonamides {1-[(2-nitrophenyl)sulfonyl]pyrrolidine, C₁₀H₁₂N₂O₄S, 1, 1-[(2-nitrophenyl)sulfonyl]piperidine, C₁₁H₁₄N₂O₄S, 2, and 1-[(2-nitrophenyl)sulfonyl]-2,3-dihydro-1H-indole, C₁₄H₁₂N₂O₄S, 3} and three N-cycloamino-o-sulfanilamides [2-(pyrrolidine-1-sulfonyl)aniline, C₁₀H₁₄N₂O₂S, 4, 2-(piperidine-1-sulfonyl)aniline, C₁₁H₁₆N₂O₂S, 5, and 2-(2,3-dihydro-1H-indole-1-sulfonyl)aniline, C₁₄H₁₄N₂O₂S, 6] suggested that forces such as hydrogen bonding and π-π interactions hold molecules together and further showed that charge transfer could promote bioactivity and the ability to form biological interactions at the piperidinyl and phenyl moieties.

Keywords: DFT; SC-XRD; crystal structure; cycloamino; inhibitory activity; nitrosulfonamide; packing architecture; sulfanilamide.