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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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Molecular structure of the primary sulfonamides and lactams used in this study to make binary cocrystals.
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fig2: Molecular structure of the primary sulfonamides and lactams used in this study to make binary cocrystals.

Mentions: Primary sulfonamides attached to a substituted phenyl ring were selected in this exploratory cocrystal study to identify the basic heterosynthons with amides in a non-competitive environment. We were successful in obtaining cocrystals of a few benzene sulfonamides with lactams (syn amides) listed in Fig. 2 ▸. A reason to choose cyclic amides over primary amides was that the latter have syn and anti N—H donors, and together with primary sulfonamide, which also has syn and anti N—H donors, the diversity of hydrogen bond motifs may become too complex for systematic analysis. In a recent study of lactams with carboxylic acids, Moragues-Bartolome et al. (2012 ▸) found that 2-pyrrolidone showed a heterotetramer (CONH⋯COOH), whereas δ-valerolactam has a homotetramer synthon (CONH⋯CONH), although there were some mixed results as well (Moragues-Bartolome et al., 2012 ▸). We report in this paper isostructural pairs of cocrystals (sulfonamide–lactam) having isosynthons (similar supramolecular synthons). The lattice parameters and crystal packing of the X-ray crystal structures suggest that there are three sets of isostructural compounds and that each set has its own isosynthons. Primary sulfonamides consist of two acceptor O atoms and two donor H atoms (SO2NH2), and the complementary functional group lactam (HN—C=O) also has one donor and one acceptor.


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

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

Molecular structure of the primary sulfonamides and lactams used in this study to make binary cocrystals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Molecular structure of the primary sulfonamides and lactams used in this study to make binary cocrystals.
Mentions: Primary sulfonamides attached to a substituted phenyl ring were selected in this exploratory cocrystal study to identify the basic heterosynthons with amides in a non-competitive environment. We were successful in obtaining cocrystals of a few benzene sulfonamides with lactams (syn amides) listed in Fig. 2 ▸. A reason to choose cyclic amides over primary amides was that the latter have syn and anti N—H donors, and together with primary sulfonamide, which also has syn and anti N—H donors, the diversity of hydrogen bond motifs may become too complex for systematic analysis. In a recent study of lactams with carboxylic acids, Moragues-Bartolome et al. (2012 ▸) found that 2-pyrrolidone showed a heterotetramer (CONH⋯COOH), whereas δ-valerolactam has a homotetramer synthon (CONH⋯CONH), although there were some mixed results as well (Moragues-Bartolome et al., 2012 ▸). We report in this paper isostructural pairs of cocrystals (sulfonamide–lactam) having isosynthons (similar supramolecular synthons). The lattice parameters and crystal packing of the X-ray crystal structures suggest that there are three sets of isostructural compounds and that each set has its own isosynthons. Primary sulfonamides consist of two acceptor O atoms and two donor H atoms (SO2NH2), and the complementary functional group lactam (HN—C=O) also has one donor and one acceptor.

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