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Modularity and three-dimensional isostructurality of novel synthons in sulfonamide-lactam cocrystals.

Bolla G, Mittapalli S, Nangia A - IUCrJ (2015)

Bottom Line: Synthon 1: catemer synthon C 2 (1)(4) chain motif, synthon 2: dimer-cyclic ring synthon R 2 (2)(8)R 4 (2)(8) motifs, and synthon 3: dimer-catemer synthon of R 2 (2)(8)C 1 (1)(4)D notation.These heterosynthons of the cocrystals observed in this study are compared with the N-H⋯O dimer R 2 (2)(8) ring and C(4) chain motifs of the individual sulfonamide structures.With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Chemistry, University of Hyderabad , Prof. C. R. Rao Road, Central University PO, Hyderabad, 500 046, India.

ABSTRACT
The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide-lactam cocrystals (SO2NH2⋯CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N-H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthon C 2 (1)(4) chain motif, synthon 2: dimer-cyclic ring synthon R 2 (2)(8)R 4 (2)(8) motifs, and synthon 3: dimer-catemer synthon of R 2 (2)(8)C 1 (1)(4)D notation. These heterosynthons of the cocrystals observed in this study are compared with the N-H⋯O dimer R 2 (2)(8) ring and C(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide-lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.

No MeSH data available.


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(a) Hirshfeld surfaces of the three types of the synthons present in sulfonamide–lactam cocrystals. (b) Two-dimensional fingerprint plots of the intermolecular contacts in the 4BrBSA–CPR cocrystal.
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fig8: (a) Hirshfeld surfaces of the three types of the synthons present in sulfonamide–lactam cocrystals. (b) Two-dimensional fingerprint plots of the intermolecular contacts in the 4BrBSA–CPR cocrystal.

Mentions: The Hirshfeld surface (using Crystal Explorer, Version 3.1, Hirshfeld, 1977 ▸; Hirshfeld & Mirsky, 1979 ▸; Kitaigorodsky, 1973 ▸; Vainshtein et al., 1982 ▸; Spackman & Jayatilaka, 2009 ▸, McKinnon et al., 1998 ▸) translates the electron density into molecular fragments and also volume around a molecule in a manner similar to the van der Waals surface, or an outer surface of the electron density in a crystal structure. The Hirshfeld surface is related to the molecule and the proximity of its nearest neighbors and this allows easy identification of characteristic strong and weak interactions throughout the structure. It explains the nature of intermolecular interactions within a crystal structure using a two-dimensional fingerprint plot consisting of spikes and wings. The 4BrBSA–VLM cocrystal two-dimensional finger plots with all types of interactions are shown in Fig. 8 ▸ as a representative of this class. The other binary systems are shown in Fig. S6. The strong spikes at 1.0–1.2 Å correspond to H⋯O interactions and the weak spikes between 1.2 and 1.4 Å for H⋯N hydrogen bonds. The other H⋯X, H⋯H, H⋯C interactions occur between 1.5 and 2.4 Å in the wings region. The strong H⋯O interaction is the major contributor in cocrystal structures (Fig. S7 and Table S3).


Modularity and three-dimensional isostructurality of novel synthons in sulfonamide-lactam cocrystals.

Bolla G, Mittapalli S, Nangia A - IUCrJ (2015)

(a) Hirshfeld surfaces of the three types of the synthons present in sulfonamide–lactam cocrystals. (b) Two-dimensional fingerprint plots of the intermolecular contacts in the 4BrBSA–CPR cocrystal.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4491311&req=5

fig8: (a) Hirshfeld surfaces of the three types of the synthons present in sulfonamide–lactam cocrystals. (b) Two-dimensional fingerprint plots of the intermolecular contacts in the 4BrBSA–CPR cocrystal.
Mentions: The Hirshfeld surface (using Crystal Explorer, Version 3.1, Hirshfeld, 1977 ▸; Hirshfeld & Mirsky, 1979 ▸; Kitaigorodsky, 1973 ▸; Vainshtein et al., 1982 ▸; Spackman & Jayatilaka, 2009 ▸, McKinnon et al., 1998 ▸) translates the electron density into molecular fragments and also volume around a molecule in a manner similar to the van der Waals surface, or an outer surface of the electron density in a crystal structure. The Hirshfeld surface is related to the molecule and the proximity of its nearest neighbors and this allows easy identification of characteristic strong and weak interactions throughout the structure. It explains the nature of intermolecular interactions within a crystal structure using a two-dimensional fingerprint plot consisting of spikes and wings. The 4BrBSA–VLM cocrystal two-dimensional finger plots with all types of interactions are shown in Fig. 8 ▸ as a representative of this class. The other binary systems are shown in Fig. S6. The strong spikes at 1.0–1.2 Å correspond to H⋯O interactions and the weak spikes between 1.2 and 1.4 Å for H⋯N hydrogen bonds. The other H⋯X, H⋯H, H⋯C interactions occur between 1.5 and 2.4 Å in the wings region. The strong H⋯O interaction is the major contributor in cocrystal structures (Fig. S7 and Table S3).

Bottom Line: Synthon 1: catemer synthon C 2 (1)(4) chain motif, synthon 2: dimer-cyclic ring synthon R 2 (2)(8)R 4 (2)(8) motifs, and synthon 3: dimer-catemer synthon of R 2 (2)(8)C 1 (1)(4)D notation.These heterosynthons of the cocrystals observed in this study are compared with the N-H⋯O dimer R 2 (2)(8) ring and C(4) chain motifs of the individual sulfonamide structures.With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Chemistry, University of Hyderabad , Prof. C. R. Rao Road, Central University PO, Hyderabad, 500 046, India.

ABSTRACT
The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide-lactam cocrystals (SO2NH2⋯CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N-H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthon C 2 (1)(4) chain motif, synthon 2: dimer-cyclic ring synthon R 2 (2)(8)R 4 (2)(8) motifs, and synthon 3: dimer-catemer synthon of R 2 (2)(8)C 1 (1)(4)D notation. These heterosynthons of the cocrystals observed in this study are compared with the N-H⋯O dimer R 2 (2)(8) ring and C(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide-lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.

No MeSH data available.


Related in: MedlinePlus