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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: 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.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.

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

Classification of three novel synthons in sulfonamide–lactam cocrystals. Names of the cocrystal structures are shown in the bottom row.
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fig3: Classification of three novel synthons in sulfonamide–lactam cocrystals. Names of the cocrystal structures are shown in the bottom row.

Mentions: A few benzene sulfonamides (listed in Fig. 2 ▸) were selected to make cocrystals with PYR, VLM, CPR and AZL cyclic amides in a 1:1 stoichiometric ratio, which were ground mechanochemically through solvent-assisted grinding to obtain cocrystals. The resulting binary systems were analyzed with greater emphasis on VLM and CPR cocrystals since they are pharmaceutically acceptable coformers. Three types of synthons were observed: synthon 1 or the catemer motif of graph-set C21(4) (Etter et al., 1990 ▸; Bernstein et al., 1995 ▸), synthon 2 which is a dimer–cyclic synthon motif of R22(8)R42(8), and synthon 3 as a dimer–catemer motif R22(8)C11(4)D (Fig. 3 ▸). The crystal structure of BSA with AZL contains synthon 2. The crystal structures of other primary sulfonamides with AZL, PYR etc. will be discussed separately. Cocrystals of celecoxib (SO2NH2 drug) with odd/even homolog cyclic amides (Bolla et al., 2014 ▸) indicated that the odd ring size coformer (PYR, CPR) follows the heterosynthon, whereas even ring lactams (VLM, AZL) result in dimer–dimer/dimer–catemer synthons. With the aim of establishing a trend for sulfonamides, this study however did not give the previously observed synthons but resulted in different motifs. A robust and predictable functional group for sulfonamide cocrystals is pyridine N-oxide coformers (as well as P- and As-oxide) (e.g. Goud et al., 2011 ▸; Croker et al., 2012 ▸; Ferguson et al., 1989 ▸; Denise et al., 2014 ▸), but these are not of practical use as pharmaceuticals since they are not GRAS molecules (generally regarded as safe). The cocrystals obtained in this study and synthon classification are summarized in Fig. 3 ▸, along with crystallographic parameters in Table 2 ▸ (additional data in Table 3 ▸).


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

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

Classification of three novel synthons in sulfonamide–lactam cocrystals. Names of the cocrystal structures are shown in the bottom row.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Classification of three novel synthons in sulfonamide–lactam cocrystals. Names of the cocrystal structures are shown in the bottom row.
Mentions: A few benzene sulfonamides (listed in Fig. 2 ▸) were selected to make cocrystals with PYR, VLM, CPR and AZL cyclic amides in a 1:1 stoichiometric ratio, which were ground mechanochemically through solvent-assisted grinding to obtain cocrystals. The resulting binary systems were analyzed with greater emphasis on VLM and CPR cocrystals since they are pharmaceutically acceptable coformers. Three types of synthons were observed: synthon 1 or the catemer motif of graph-set C21(4) (Etter et al., 1990 ▸; Bernstein et al., 1995 ▸), synthon 2 which is a dimer–cyclic synthon motif of R22(8)R42(8), and synthon 3 as a dimer–catemer motif R22(8)C11(4)D (Fig. 3 ▸). The crystal structure of BSA with AZL contains synthon 2. The crystal structures of other primary sulfonamides with AZL, PYR etc. will be discussed separately. Cocrystals of celecoxib (SO2NH2 drug) with odd/even homolog cyclic amides (Bolla et al., 2014 ▸) indicated that the odd ring size coformer (PYR, CPR) follows the heterosynthon, whereas even ring lactams (VLM, AZL) result in dimer–dimer/dimer–catemer synthons. With the aim of establishing a trend for sulfonamides, this study however did not give the previously observed synthons but resulted in different motifs. A robust and predictable functional group for sulfonamide cocrystals is pyridine N-oxide coformers (as well as P- and As-oxide) (e.g. Goud et al., 2011 ▸; Croker et al., 2012 ▸; Ferguson et al., 1989 ▸; Denise et al., 2014 ▸), but these are not of practical use as pharmaceuticals since they are not GRAS molecules (generally regarded as safe). The cocrystals obtained in this study and synthon classification are summarized in Fig. 3 ▸, along with crystallographic parameters in Table 2 ▸ (additional data in Table 3 ▸).

Bottom Line: 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.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.

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