(W1130-06-34) The Influence of Single Peripheral Replacements on the Supramolecular Structures of Sulfonyl Urea Analogues: H vs. CH₃ vs. Cl vs. Br

Purpose: Compounds containing sulfonyl urea as the structural core have been used extensively for the treatment of Type II diabetes, by stimulating insulin secretion from pancreatic β-cells by binding to the ATP-sensitive potassium channel. Subtle changes to the mol­ecule have shown drastic effects on its biological activity and also the arrangement of mol­ecules in the crystal structure. In this research the crystal structures of sulfonyl urea structural analogues, which differ only by a substitution at a single peripheral location on the molecule, were investigated. Substitutions allowed examination of how incremental changes affected molecular conformation and differences in intermolecular forces that affect the crystal packing.

Methods: Single crystals of 4 sulfonyl urea analogues (H = phenpropamide, CH₃ = tolpropamide, Cl = chlorpropamide, and Br = bromopropamide) were recrystallized from methanol under identical growth conditions. Single crystal X-ray diffraction data were collected at room temperature using a Bruker SMART Apex 2 CCD diffractometer. Data were generated for 25 s per frame using Mo-Kα radiation (l=0.71073 Å) at 50 kV, 30 mA, and a graphite monochromator. The Bruker SAINT program was used for data integration and empirical absorption correction was performed using the SADABS program. The space groups were assigned by direct methods using XPREP within the SAINT suite, while structures were solved using the SHELXS v 2013/1, subject to refinement in SHELXL v.2018/3 by full-matrix least squares on F2 with all reflections. Molecular conformation analyses for analogues was performed using the Mercury platform. Hirshfeld surface analysis was carried out for all independent molecules in the asymmetric unit using CrystalExplorer17.5 mapped over d_norm, which was estimated by the calculations of the external and inter­nal distances to the nearest nucleus. Hirshfeld surfaces and their associated 2-dimensional fingerprint plots were used to qu­antify the various inter­molecular inter­actions.

Results: All sulfonylurea analogues have 2 hydrogen bond donors in the same relative positions. Chlorpropamide and bromopropamide also contain peripheral halogen atoms, which act as halogen bond donors. The tolpropamide and bromopropamide molecules grew in the monoclinic space groups P2₁/c and C2/c, respectively, whereas phenpropamide grew in the triclinic space group P-1 and chlorpropamide grew in the orthorhombic space group P2₁2₁2_1. All analogues had one molecule in the asymmetric unit except phenpropamide (Z’ = 2). In all studied crystals, the molecules exhibited similar conformations with minor differences, illustrated in the overlay diagram with the sulfonyl group as a common reference plane in Figure 1. The sulfonylurea substructure in all molecules showed similar geometrical features, possibly due to high rigidity. The aromatic group showed differences for molecule 1 of phenpropamide, where it was twisted relative to tolpropamide, chlorpropamide, and bromopropamide. In contrast, molecule 2 of phenpropamide had the same aromatic ring arrangement as the other structural analogues. The n-propyl chain adopted the staggered configuration for all analogues so as to be in the most stable energy state. Although the orientation of the n-propyl chain changed between the molecules, the bond angles were comparable, highlighting that the difference was only due to its flexibility. The fingerprint analyses provided deeper insights into the classification of the intermolecular interactions for the structural analogues. The relative contribution to the Hirshfeld surface area was quantified for all analogues (Figure 2). Overall, within the structural analogues the H…H contacts claim the highest contribution. However, when comparing between the analogues the rank order for H…H contacts was tolpropamide >phenpropamide molecule 2 >phenpropamide molecule 1 >chlorpropamide > bromopropamide. The O…H/H…O contacts (representing hydrogen bonds) were lower for halogenated compounds relative to non-halogenated analogues. Bromopropamide and chlorpropamide showed additional halogen-related contacts occupying the Hirshfeld surface. Additionally, bromopropamide showed a significant contribution through the Br…O/O…Br contacts (4.3%), suggesting halogen bonding interactions within the crystal structure. This was further supported by the C-Br…O bond angle of 163.03° and Br…O distance of 3.442 Å, both of which fell in the reported geometric range of Br…O type halogen bonds.

Conclusion: The crystal structures of phenpropamide, tolpropamide, chlorpropamide, and bromopropamide were solved and refined. The differences observed in the space groups highlighted that although all structural analogues were grown under similar conditions, the crystals were not isostructural, owing to differences in non-covalent interactions in the supramolecular structure. Overall, the molecular conformations for all molecules were similar with subtle differences. Crystallographic and computational investigations of the crystal structures of the sulfonyl urea analogues with only a single peripheral attachment difference (H vs. CH₃ vs. Cl vs. Br) illustrated how the interaction landscapes differently stabilized the crystal structures due to strong or weak hydrogen bonds, and in some cases halogen bonds.


Figure 1: Molecular overlay diagram for all sulfonyl urea structural analogues superimposing the sulfonyl group. Phenpropamide molecule 1 is shown in A) whereas phenpropamide molecule 2 is shown in B) along with tolpropamide, chlorpropamide and bromopropamide molecules. Hydrogen atoms are not shown for clarity.


Figure 2: Percentage contributions to the Hirshfeld surface area for the various close intermolecular contacts in molecules 1 and 2 of phenpropamide, tolpropamide, chlorpropamide, and bromopropamide.