T3P-Promoted Synthesis of a Series of 2-Aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones and Their Activity against the Kinetoplastid Parasite Trypanosoma brucei.

A series of fourteen 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thionicotinic acid, two difficult substrates. The reactions were operationally simple, did not require specialized equipment or anhydrous solvents, could be performed as either two or three component reactions, and gave moderate-good yields as high as 63%. This provides ready access to N-phenyl compounds in this family, which have been generally difficult to prepare. As part of the study, the first crystal structure of neutral thionicotinic acid is also reported, and showed the molecule to be in the form of the thione tautomer. Additionally, the synthesized compounds were tested against T. brucei, the causative agent of Human African Sleeping Sickness. Screening at 50 µM concentration showed that five of the compounds strongly inhibited growth and killed parasites.

2,3-Diphenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one.

The six-membered thia-zine ring in the title compound, C16H15NOS, adopts a half-chair conformation, with the S atom forming the back of the chair. The base of the chair has a slight twist reflected in the r.m.s. deviation (0.0756 Å) of those five atoms from the plane defined by them. The phenyl substituents are almost perpendicular to each other [dihedral angle 87.06 (9)°]. In the crystal, mol-ecules are linked into chains parallel to the c axis through C-H⋯O inter-actions.

2,3-Diphenyl-1,3-thia-zolidin-4-one.

The title compound, C15H13NOS, is a chiral mol-ecule crystallized as a racemate, with two molecules in the asymmetric unit. In each of the mol-ecules, the five-membered thia-zine ring has an envelope conformation, with the S atom forming the flap. In one mol-ecule, the angle between the two phenyl-ring planes is 82.77 (7)°, while in the other it is 89.12 (6)°. In the crystal, mol-ecules are linked into chains along the b-axis direction by C-H⋯O hydrogen bonds.

2,3-Diphenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one.

In the racemic title compound, C19H14N2OS, the two phenyl substituents on the 1,3-thia-zine ring are almost perpendicular to the pyridine ring which is fused to the thia-zine ring [inter-ring dihedral angles = 87.90 (8) and 85.54 (7)°]. The dihedral angle between the two phenyl rings is 75.11 (7)°. The six-membered thia-zine ring has an envelope conformation with the ortho-related C atom forming the flap. The crystals exhibit face-to-edge aromatic-ring interactions with the nearest C-H⋯C distance equal to 3.676 (3) Å.

2,3-Diphenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one.

In the title compound, C20H15NOS, the dihedral angle between the phenyl rings is 74.25 (6)°. The six-membered 1,3-thia-zine ring has an envelope conformation with the C atom at the 2-position forming the flap. The crystal structure features weak C-H⋯O inter-actions, which lead to the formation of a tape motif along [110].

Synthesis and crystal structures of two racemic 2-heteroaryl-3-phenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-ones.

3-Phenyl-2-(thio-phen-3-yl)-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one (C17H12N2OS2, 1) and 2-(1H-indol-3-yl)-3-phenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one 0.438-hydrate (C21H15N3OS·0.438H2O, 2) crystallize in space groups P21/n and C2/c, respectively. The asymmetric unit in each case is comprised of two parent mol-ecules, albeit of mixed chirality in the case of 1 and of similar chirality in 2 with the enanti-omers occupying the neighboring asymmetric units. Structure 2 also has water mol-ecules (partial occupancies) that form continuous channels along the b -axis direction. The thia-zine rings in both structures exhibit an envelope conformation. Inter-molecular inter-actions in 1 are defined only by C-H⋯O and C-H⋯N hydrogen bonds between crystallographically independent mol-ecules. In 2, hydrogen bonds of the type N-H⋯O between independent mol-ecules and C-H⋯N(π) type, and π-π stacking inter-actions between the pyridine rings of symmetry-related mol-ecules are observed.

6,7-Diphenyl-5-thia-7-aza-spiro-[2.6]nonan-8-one.

The asymmetric unit of the title compound, C19H19NOS, contains two independent mol-ecules (A and B), in both of which the 1,3-thia-zepan-4-one ring adopts a chair-type conformation. The dihedral angles between the two phenyl rings are 65.28 (8) and 60.31 (9)° for mol-ecules A and B, respectively. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, resulting in a three-dimensional network.

2-(3-Nitro-phen-yl)-3-phenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one.

The title compound, C20H14N2O3S, has three aromatic rings, viz. (i) a phenyl ring, (ii) a 3-nitro-phenyl and (iii) a 1,3-benzo-thia-zine fused-ring system. The dihedral angle between (i) and (ii) is 85.31 (15)°, between (ii) and (iii) is 81.33 (15)° and between (i) and (iii) is 75.73 (15)°. The six-membered 1,3-thia-zine ring has an envelope conformation with the C atom in the 2-position forming the flap. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming a three-dimensional network.

6,7-Diphenyl-5-thia-7-aza-spiro-[2.6]nonan-8-one 5,5-dioxide.

The racemic mixture of the title compound, C19H19NO3S, crystallizes in space group P with two homochiral mol-ecules in each asymmetric unit. The seven-membered ring in both mol-ecules is in a pucker-chair conformation. The extended structure exhibits C-H⋯O hydrogen bonds, of which two connect crystallographically independent mol-ecules to generate a chain propagating along the b-axis direction. One C-H grouping of the cyclo-propyl ring is in close contact with the phenyl ring of the neighboring independent mol-ecule in C-H⋯π type inter-actions with carbon atom-ring-centroid distances of 3.544 (5) and 3.596 (4) Å. Other inter-actions are of the parallel-reciprocal type, with the chiral carbon atom of one mol-ecule donating a proton to an oxygen atom of the sulfone group of a symmetry-related mol-ecule and vice-versa. Symmetry-related mol-ecular pairs also exhibit T-type inter-actions between aromatic rings with inter-planar angles of 74.2 (2) and 69.2 (2)° and inter-centroid distances of 4.965 (4) and 5.114 (4) Å.

Crystal structures of rac-2,3-diphenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zine-1,1,4-trione and N-[(2S,5R)-1,1,4-trioxo-2,3-diphenyl-1,3-thia-zinan-5-yl]acet-amide.

The syntheses and crystal structures of two thia-zinone compounds, namely, rac-2,3-diphenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zine-1,1,4-trione, C16H15NO3S, in its racemic form, and N-[(2S,5R)-1,1,4-trioxo-2,3-diphenyl-1,3-thia-zinan-5-yl]acet-amide, C18H18N2O4S, in an enanti-opure form, are reported. The thia-zine rings in the two structures differ in their puckering, as a half-chair in the first and a boat pucker in the second. The extended structures for both compounds have only C-H⋯O-type inter-actions between symmetry-related mol-ecules, and exhibit no π-π stacking inter-actions in spite of each having two phenyl rings.

Crystal structures of the sulfones of 2,3-diphenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one and 2,3-diphenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one.

The title sulfones, 2,3-diphenyl-2,3-di-hydro-4H-1,3-benzo-thia-zine-1,1,4-trione, C20H15NO3S, and 2,3-diphenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zine-1,1,4-trione, C19H14N2O3S, crystallize in space group P21/n with two mol-ecules in each of the asymmetric units and have almost identical unit cells and extended structures. In both structures, the thia-zine rings exhibit a screw-boat pucker. The inter-molecular inter-actions observed are C-H⋯O-type hydrogen bonds and parallel partial π-π stacking between the fused aromatic rings (benzo- or pyrido-) of the core of the mol-ecules within each asymmetric unit, and also connecting to mol-ecules with translational periodicity in the a-axis direction in what can be described as columns (two per asymmetric unit) of stacked mol-ecules with alternating chirality. The pendant phenyl groups of both mol-ecules do not participate in aromatic ring inter-actions.

Synthesis and crystal structure of racemic (R*,R*)-2,2'-(1,4-phenyl-ene)bis-(3-phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one).

In the racemic title compound, C26H24N2O2S2, one of the thia-zine rings shows a twisted boat conformation (Q = 0.743 Å, θ = 92.1°) and the other a half-chair puckering (Q = 0.669 Å, θ = 54.3°). The terminal phenyl rings are almost parallel to each other [dihedral angle 21.71 (10)°]. Both of these rings are orthogonal to the central phenyl ring, subtending a dihedral angle of about 78° in each case. The extended structure is consolidated by C-H⋯O and C-H⋯S hydrogen bonds as well as aromatic ring inter-actions of parallel-displaced and T-type. The mol-ecule has approximate C2 local symmetry but this is not carried over to its three-dimensional structure or the inter-molecular inter-actions.

2,3-Diphenyl-2,3-dihydro-4H-1,3-thiaza-4-one heterocycles inhibit growth and block completion of cytokinesis in kinetoplastid parasites.

Kinetoplastid parasites are model eukaryotes with a complex cell cycle that is highly regulated both spatially and temporally. In addition, diseases caused by these parasites continue to have a significant impact on human and animal health worldwide. While there have been advancements in chemotherapy for these diseases, there is a continual need for an arsenal of compounds that have robust anti-parasite activity with minimal impact on the human host. While investigating a series of 2,3-diphenyl-2,3-dihydro-4H-1,3-thiaza-4-one heterocycles with potential activity against these parasites, we found a pyridothiazinone that inhibits growth of the monoxenous parasite Crithidia fasciculata and two life cycle stages of Trypanosoma brucei. This inhibition is more pronounced in T. brucei and is associated with an unusual pre-abscission cell cycle arrest. Exploring the mode of action for these and related compounds in kinetoplastids may provide tools with which to explore cell cycle regulation in these important organisms.

Crystal structures of two isomeric 2-aryl-3-phenyl-1,3-thia-zepan-4-ones.

The crystal of 6-(3-nitro-phen-yl)-7-phenyl-5-thia-7-aza-spiro-[2.6]nonan-8-one (1), C19H18N2O3S, has monoclinic (P21/n) symmetry while that of its isomer 6-(4-nitro-phen-yl)-7-phenyl-5-thia-7-aza-spiro-[2.6]nonan-8-one (2), has ortho-rhom-bic (Pca21) symmetry: compound 1 has two mol-ecules, A and B, in the asymmetric unit while 2 has one. In all three mol-ecules, the seven-membered thia-zepan ring exhibits a chair conformation with Q2 and Q3 values (Å) of 0.521 (3), 0.735 (3) and 0.485 (3), 0.749 (3) in 1 and 0.517 (5), 0.699 (5) in 2. In each structure, the phenyl rings attached to adjacent atoms of the thia-zepan ring have inter-planar angles ranging between 41 and 47°. Except for the nitro groups, the three mol-ecules have similar conformations when overlayed in pairs. Both crystal structures are consolidated by C-H⋯O hydrogen bonds.

Crystal structures of two solvated 2-aryl-3-phenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-ones.

The synthesis and crystal structures of 2-(4-fluoro-phen-yl)-3-phenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one toluene hemisolvate (1), C19H13FN2OS·0.5C7H8, and 2-(4-nitro-phen-yl)-3-phenyl-2,3-di-hydro-4H-pyrido[3,2-e][1,3]thia-zin-4-one iso-propanol 0.25-solvate 0.0625-hydrate (2), C19H13N3O3S·0.25C3H7O·0.0625H2O, are reported. Both are racemic mixtures (centrosymmetric crystal structures) of the individual com-pounds and incorporate solvent mol-ecules in their structures. Compound 2 has four thia-zine mol-ecules in the asymmetric unit. All the thia-zine rings in this study show an envelope pucker, with the C atom bearing the substituted phenyl ring displaced from the other atoms. The phenyl and aryl rings in each of the mol-ecules are roughly orthogonal to each other, with dihedral angles of about 75°. The extended structures of 1 and 2 are consolidated by C-H⋯O and C-H⋯N(π), as well as T-type (C-H⋯π) inter-actions. Parallel aromatic ring inter-actions (π-π stacking) are observed only in 2.

Crystal structure of meso-3,3'-(1,4-phenyl-ene)bis-(2-phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one).

The crystal structure of the title compound - meso-C26H24N2O2S2 with two stereocenters - has half the mol-ecule in the asymmetric unit with the other half generated by a crystallographic center of inversion. The thia-zine ring is in a conformation that is between half-chair and envelope [θ = 52.51 (17)°]. The phenyl ring on the 2-carbon atom of the thia-zine ring is pseudo-axial. The central phenyl ring of the mol-ecule is close to orthogonal to the phenyl rings on either side with an angle of 76.85 (11)° between those planes. In the crystal, pairwise, weak C-H⋯O hydrogen bonds between the central phenyl ring and the oxygen atoms of neighboring mol-ecules result in continuous strips propagating along the a-axis direction. Hydro-phobic inter-actions of the C-H⋯π type are also observed.

Crystal structures of two 2,3-diaryl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-ones.

The syntheses and crystal structures of 2,3-bis-[3-(tri-fluoro-meth-yl)phen-yl]-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one (di-m-CF3; C22H13F6NOS) (1) and 2,3-bis-(4-methyl-phen-yl)-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one (di-p-CH3; C22H19NOS) (2) are reported. Each structure is racemic: the asymmetric unit of 2 consists of two mol-ecules. In both 1 and 2, the six-membered 1,3-thia-zine ring is close to an envelope conformation with the chiral C atom forming the flap. In 1, the 2-aryl group is pseudo-equatorial, while in 2 it is pseudo-axial. In 1, the pendant aryl rings form a V shape with an inter-centroid distance of 3.938 (3) Šand an acute dihedral angle of 48.3 (2)° between them. Both CF3 groups are disordered over two orientations in 0.687 (19):0.313 (19) and 0.667 (16):0.33 (16) ratios. In each of the independent mol-ecules of 2, the aryl rings are almost orthogonal to each other [dihedral angles = 85.50 (12) and 86.07 (11)°]. In both structures, the chiral C atom and the O atoms participate in C-H⋯O-type hydrogen bonding between symmetry-related mol-ecules of 1 or the independent enanti-omers in 2, forming chains along the c-axis direction in 1 and the b-axis direction in 2. Additionally, in 1, π-π contacts of both face-to-face and edge-to-face type, as well as π-H⋯O and π-H⋯F inter-actions are observed. In 2, a racemic mixture of mol-ecules forms layers in the ac plane linked by weak π-π and C-H⋯π inter-actions.

Spontaneous resolution and crystal structure of (2S)-2-(3-nitro-phen-yl)-3-phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one; crystal structure of rac-2-(4-nitro-phen-yl)-3-phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one.

The crystal structures of isomeric rac-2-(4-nitro-phen-yl)-3-phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one (C16H14N2O3S) (1) and (2S)-2-(3-nitro-phen-yl)-3-phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one (C16H14N2O3S) (2) are reported here. While 1 crystallizes in a centrosymmetric space group, the crystal of 2 chosen for data collection has mol-ecules only with (2S) chirality. This is the result of spontaneous resolution during crystallization, as the synthesis produces a racemic mixture. A crystal with (2R) mol-ecules was also found in the same crystallization vial (structure factors available). The six-membered thia-zine ring in both 1 and 2 displays an envelope conformation with the S atom forming the flap. The aryl rings in both structures adopt an approximate V shape with angles between their planes of 46.97 (14)° in 1 and 58.37 (10)° in 2. In both structures, the mol-ecules form layers in the ab plane. Within such a layer in 1, one of the O atoms of the nitro-phenyl group accepts a C-H⋯O hydrogen bond from the CH group at position 5 of the thia-zine ring of a mol-ecule of opposite chirality, forming chains along the a-axis direction. Each of the thia-zine rings also participate in C-H⋯O bonds with the same carbon atom as above, resulting in chains along the b-axis direction, albeit of monochiral type. Adjacent layers are consolidated along the c-axis direction by pairs of parallel hydrogen bonds (C-H⋯O type) between the nitro-phenyl groups of enanti-omers. In 2, the two C-H⋯O hydrogen bonds contribute to chain formation along the b-axis direction. Weak edge-to-face inter-actions between the aryl groups of neighbouring mol-ecules in 1, and C-H⋯π inter-actions between a thia-zine ring CH group and a phenyl group of a neighboring mol-ecule in 2 are also observed.

Crystal structures of two 1,3-thia-zolidin-4-one derivatives featuring sulfide and sulfone functional groups.

The crystal structures of two closely related compounds, 1-cyclo-hexyl-2-(2-nitro-phen-yl)-1,3-thia-zolidin-4-one, C15H18N2O3S, (1) and 1-cyclo-hexyl-2-(2-nitro-phen-yl)-1,3-thia-zolidin-4-one 1,1-dioxide, C15H18N2O5S, (2), are presented. These compounds are comprised of three types of rings: thia-zolidinone, nitrophenyl and cyclo-hexyl. In both structures, the rings are close to mutually perpendicular, with inter-planar dihedral angles greater than 80° in each case. The thia-zol-idinone rings in both structures exhibit envelope puckering with the S atom as flap and the cyclo-hexyl rings are in their expected chair conformations. The two structures superpose fairly well, except for the orientation of the nitro groups with respect to their host phenyl ring, with a difference of about 10° between 1 and 2. The extended structure of 1 has two kinds of weak C-H⋯O inter-actions, giving rise to a closed ring formation involving three symmetry-related mol-ecules. Structure 2 has four C-H⋯O inter-actions, two of which are exclusively between symmetry-related thia-zolidinone dioxide moieties and have a parallel 'give-and-take-fashion' counterpart. In the other two inter-actions, the nitrophenyl ring and the cyclo-hexane ring each offer an H atom to the two O atoms on the sulfone group. Additionally, a C-H⋯π inter-action between a C-H group of the cyclo-hexane ring and the nitrophenyl ring of an adjacent mol-ecule helps to consolidate the structure.

Crystal structure of (1S,2S,5R)-5-acetyl-amino-4-oxo-2,3-diphenyl-1,3-thia-zinan-1-ium-1-olate.

The asymmetric unit of the enanti-omerically pure title compound, C18H18N2O3S, comprises two independent mol-ecules (A and B) having almost identical conformations. When overlayed, the alignment-r.m.s. deviation value is 0.30 Å. The six-membered heterocycle has a twisted half-chair conformation in both mol-ecules. The O atom on the S atom of the ring is pseudo-axial on the thia-zine ring and trans to both a phenyl group substituent and the acetamide group in each case. The two benzene rings in each mol-ecule are almost orthogonal to each other, with inter-planar dihedral angles of 83.79 (17) and 86.95 (16)°. The acetamide group is pseudo-equatorial and a phenyl ring is pseudo-axial on the thia-zine ring. Both mol-ecules show a weak intra-molecular C-H⋯O inter-action between H-atom donors of one of the phenyl rings and the acetamide group. In the crystal, an inter-molecular N-H⋯O(thia-zine) hydrogen bond links B mol-ecules along the 21 (b) screw axis and, in addition, an N-H⋯O(acetamide) hydrogen bond links A and B mol-ecules across a. A two-dimensional layered structure lying parallel to (001) is generated, also involving weak inter-molecular C-H⋯O inter-actions.