SO2 NH Research Articles

N-(2-Chlorophenyl)-2,4-dimethylbenzenesulfonamide

In the title compound, C14H14ClNO2S, the conformation of the N—C bond in the C—SO2—NH—C segment has gauche torsions with respect to the S=O bonds. The mol­ecule is bent at the S atom with a C—SO2—NH—C torsion angle of −54.9 (2)°. The sulfonyl and aniline benzene rings are rotated relative to each other by 75.7 (1)°. An intra­molecular N—H⋯Cl hydrogen bond is present. In the crystal, inter­molecular N—H⋯O hydrogen-bonding inter­actions are observed and the mol­ecules are packed into chains parallel to the b axis.

N-Benzoyl-2-methylbenzenesulfonamide

In the title compound, C14H13NO3S, the conformation of the N—H bond in the C—SO2—NH—C(O) segment is anti to the C=O bond. The tolyl and benzoyl groups are twisted about the S—N bond, with a C—S—N—C torsion angle of 68.8 (4)°. The dihedral angle between the sulfonyl and the benzoyl benzene rings is 73.9 (1)°. In the crystal, the mol­ecules are linked into C(4) chains along the c axis by N—H⋯O hydrogen bonds.

Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: Dual Inhibitors of cyclooxygenases and 5-lipoxygenase

A new group of acetic acid ( 7a– c, R 1 = H), and propionic acid ( 7d– f, R 1 = Me), regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compounds exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isozyme. Attachment of the N-difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, that is, absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl)acetic acid ( 7c) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Molecular modeling (docking) studies showed that the highly electronegative CHF 2 substituent present in 7c, that showed a modest selectivity for the COX-2 isozyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO 2NH 2) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region containing the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs.

N-(2,5-Dichlorophenyl)benzenesulfonamide

In the title compound, C12H9Cl2NO2S, the conformation of the N—H bond is syn to the 2-chloro group and anti to the 3-chloro group of the aniline benzene ring. The mol­ecule is bent at the S atom with a C—SO2—NH—C torsion angle of 66.4 (2)°. The two rings form a dihedral angle of 73.3 (1)° and an intra­molecular N—H⋯Cl hydrogen bond occurs. The crystal structure features chains linked by N—H⋯O hydrogen bonds.

Molecular structure, p K a, lipophilicity, solubility and absorption of biologically active aromatic and heterocyclic sulfonamides

The methods of theoretical chemistry have been used to elucidate molecular properties of clinically useful acetazolamide, dorzolamide and brinzolamide and two new aromatic sulfonamides in both neutral and deprotonated forms. The geometries and energies of these drugs have been computed using HF/6–31G(d), Becke3LYP/6–31G(d) and Becke3LYP/6–311+G(d,p) model chemistries. The equilibrium structure of the acetazolamide is stabilized via intramolecular interaction between non-bonded S···O atoms of the acetylamino group and the thiadiazole ring. In the case of the aromatic sulfonamides (4-sulfamoyl- N-(3-morpholinopropyl) benzamide (P10), and N-(morpholinopropyl)benzene-1,4-bis(sulfonamide) (P20)) the fully optimized most stable conformers possess characteristic L-shape structure stabilized via intramolecular hydrogen bonding system of the N–H···N type. Computed partition coefficients (XLOGP2 method) for drugs studied varied between –0.3 and –1.8. Neutral compounds are described as slightly lipophilic drugs. The calculated water solubility of dorzolamide and brinzolamide is comparably low. P10 and P20 are slightly lipophilic sulfonamides with moderate solubility. The calculated p K a values of –SO 2NH 2 moiety in the sulfonamides studied are in the range of 7.3–9.7 and are characterized as weak organic acids.

N,N′-Bis(phenylsulfonyl)succinamide

In the crystal structure of the title compound, C16H16N2O6S2, the conformation of the N—C bonds in the C—SO2—NH—C(O)—C segments have gauche torsions with respect to the S=O bonds, while the conformations of the N—H and C=O bonds in the amide fragments are trans to each other and the amide O atom is anti to the H atoms attached to the adjacent C atom. The mol­ecule is bent at the S atom with a C—SO2—NH—C(O) torsion angle of 65.2 (2)°. The molecule lies about a centre of inversion. The dihedral angle between the benzene ring and the SO2—NH—C(O)—C2 segment in the two halves of the mol­ecule is 77.4 (1)°. The structure exhibits both intra­molecular and inter­molecular hydrogen bonds. A series of N—H⋯O(S) hydrogen bonds links the mol­ecules into infinite chains.

Carbonic anhydrase inhibitors. X-ray crystal studies of the carbonic anhydrase II–trithiocarbonate adduct—An inhibitor mimicking the sulfonamide and urea binding to the enzyme

Trithiocarbonate ( CS 3 2 - ) inhibits with low micromolar affinities several mammalian carbonic anhydrases, CAs, EC 4.2.1.1 [Innocenti et al., Bioorg. Med. Chem. Lett. 2009, 19, 1855]. Here we report the X-ray crystal structure of the hCA II–trithiocarbonate adduct. Trithiocarbonate is monodentately bound to the Zn(II) ion and makes several hydrogen bonds with Thr199 and two water molecules from the enzyme active site. Its binding is different from that of ureate, another small inhibitor isosteric with trithiocarbonate but somehow mimicks the binding of the SO 2NH moiety present in the sulfonamide inhibitors and is similar to that of bicarbonate. Compounds incorporating this new zinc-binding group, CS 2 - , may thus lead to new classes of potent inhibitors.

N-(4-Chlorobenzoyl)benzenesulfonamide

In the crystal structure of the title compound, C13H10ClNO3S, the conformation of the N—H bond in the C—SO2—NH—C(O) segment is anti to the C=O bond. The dihedral angle between the two aromatic rings is 68.6 (1)°. The mol­ecule is twisted at the S atom with a dihedral angle of 75.7 (1)° between the sulfonyl benzene ring and the —SO2—NH—C—O segment; the dihedral angle between the latter and the benzoyl ring is 8.3 (2)°. In the crystal, mol­ecules are linked by N—H⋯O(S) hydrogen bonds.

N-(3-Chlorobenzoyl)benzenesulfonamide

In the crystal structure of the title compound, C13H10ClNO3S, the conformation of the N—H bond in the C—SO2—NH—C(O) segment is anti to the C=O bond. The dihedral angle between the two benzene rings is 87.5 (1)°. The crystal structure features inversion-related dimers linked by pairs of N—H⋯O(S) hydrogen bonds.

2,2-Dimethyl-N-(phenylsulfonyl)acetamide

In the title compound, C10H13NO3S, the N—H and C=O bonds in the SO2—NH—CO—C segment are anti to each other. The benzene ring and the SO2—NH—CO—C segment form a dihedral angle of 87.4 (1)°. The crystal packing features inversion-related dimers linked by pairs of N—H⋯O hydrogen bonds.

N-Benzoylbenzenesulfonamide

In the crystal structure of the title compound, C13H11NO3S, the conformation of the N—H bond in the C—SO2—NH—C(O)—C segment is anti to the C=O bond. The molecule is twisted at theN atom with a dihedral angle of 86.5(1)° between the sulfonyl benzene ring and the —SO2—NH—C=O segment. Furthermore, the dihedral angle between the two benzene rings is 80.3(1)°. The crystal structure features inversion-related dimers linked by pairs of N—H⋯O(S) hydrogen bonds.

N-(3,5-Dichlorophenyl)-4-methylbenzenesulfonamide

In the crystal structure of the title compound, C13H11Cl2NO2S, the conformation of the N—C bond in the C—SO2—NH—C segment is gauche with respect to the SO bonds. The two benzene rings are tilted by 79.6 (1)° relative to each other. In the crystal, inversion dimers linked by pairs of N—H⋯O hydrogen bonds occur.

N-(3,4-Dichlorophenyl)-2,4-dimethylbenzenesulfonamide

In the crystal structure of the title compound, C14H13Cl2NO2S, the configurations of the N—C bond with respect to the S=O bonds are trans and gauche. The mol­ecule is bent at the S atom with a C—SO2—NH—C torsion angle of −69.7 (2)°. The conformation of the N—H bond is syn to the 3-chloro group in the substituted aniline ring. The two benzene rings are tilted with respect to each other by 82.4 (1)°. The presence of N—H⋯O(S) hydrogen bonding packs the mol­ecules into supra­molecular chains along the b axis.

4-Chloro-N-(2-chlorophenyl)-2-methylbenzenesulfonamide

In the crystal structure of the title compound, C13H11Cl2NO2S, the conformations of the N—C bond in the C—SO2—NH—C segment are trans and gauche with respect to the S=O bonds. The C—S(O2)—N(H)—C torsion angle is 74.8 (4)°, indicating that the mol­ecule is bent at the S atom. In the crystal structure, inversion dimers linked by pairs of N—H⋯O hydrogen bonds occur. An intramolecular N—H⋯Cl inter­action is also present.

Synthesis of 1-(methanesulfonyl- and aminosulfonylphenyl)acetylenes that possess a 2-( N-difluoromethyl-1,2-dihydropyridin-2-one) pharmacophore: Evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

A hitherto unknown class of linear acetylene regioisomers were designed such that a SO 2Me or SO 2NH 2 group was located at the ortho-, meta- or para-position of the acetylene C-1 phenyl ring, and a N-difluoromethyl-1,2-dihydropyridin-2-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three SO 2Me regioisomers, and the 4-SO 2NH 2 analog, were potent inhibitors of 5-lipoxygenase (5-LOX IC 50 = 3.2–3.5 μM range) relative to the reference drug caffeic acid (IC 50 = 4.0 μM). The SO 2Me regioisomers exhibited weak cyclooxygenease-1 (COX-1) and -2 (COX-2) inhibitory activity with a modest COX-2 selectivity index. The most potent 3-SO 2Me, 4-SO 2Me and 4-SO 2NH 2 compounds, with respective ED 50 values of 66.1, 68.5 and 86.5 mg/kg po, exhibited comparable oral anti-inflammatory (AI) activity to that of the reference drug ibuprofen (ED 50 = 67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of inhibiting 5-LOX for exploitation in the development of 5-LOX inhibitory AI drugs.

2,2-Dichloro-N-(phenylsulfonyl)acetamide

The conformation of the N—H and C=O bonds in the title compound, C8H7Cl2NO3S, is trans. The benzene ring and the SO2—NH—CO—C group form a dihedral angle of 79.75 (8)°. Mol­ecules are connected via N—H⋯O hydrogen bonds to form linear supra­molecular chains.

2,2-Dichloro-N-(4-chlorophenylsulfonyl)acetamide

In the crystal structure of the title compound (N4CPSDCAA), C8H6Cl3NO3S, the conformations of the N—H and C=O bonds in the SO2—NH—CO—C group are trans to each other, similar to those observed in 2,2-dichloro-N-(phenyl­sulfon­yl)­acetamide (NPSDCAA), 2,2-dichloro-N-(4-methyl­phenyl­sulfon­yl)acetamide (N4MPSDCAA) and N-(4-chloro­phenyl­sulfon­yl)-2,2,2-trimethyl­acetamide (N4CPSTMAA), with similar bond parameters. The –SNHCOC– unit in N4CPSDCAA is essentially planar and makes a dihedral angle of 79.67 (5)° with the benzene ring, comparable to 79.75 (8)° in NPSDCAA, 81.02 (5)° in N4MPSDCAA and 82.2 (1)° in N4CPSTMAA. The mol­ecules in N4CPSDCAA are linked into layers parallel to the (001) plane by inter­molecular N—H⋯O hydrogen bonds.

2,2,2-Trimethyl-N-(4-methyl-phenyl-sulfon-yl)acetamide.

The bond parameters and conformations of the N—H and C=O bonds of the SO2—NH—CO—C group in the title compound, C12H17NO3S, anti to each other, are similar to what has been observed in related structures. The benzene ring and the SO2—NH—CO—C group make a dihedral angle of 71.2 (1)°. Inter­molecular N—H⋯O hydrogen bonds link the mol­ecules into centrosymmetric dimers.

Synthesis and biological evaluation of 1-(benzenesulfonamido)-2-[5-( N-hydroxypyridin-2(1 H)-one)]acetylene regioisomers: A novel class of 5-lipoxygenase inhibitors

A hitherto unknown class of linear acetylene regioisomers were designed such that a SO 2NH 2 group was located at the ortho-, meta-, or para-position of the acetylene C-1 phenyl ring, and a N-hydroxypyridin-2(1 H)-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three regioisomers inhibited 5-lipoxygenase (5-LOX), where the relative potency order was 2-SO 2NH 2 (IC 50 = 10 μM) >3-SO 2NH 2 (IC 50 = 15 μM) >4-SO 2NH 2 (IC 50 = 68 μM) relative to the reference drug nordihydroguaiaretic acid (NDGA; IC 50 = 35 μM). The 2-SO 2NH 2 regioisomer (ED 50 = 86.0 mg/kg po) exhibited excellent oral anti-inflammatory (AI) activity that was more potent than aspirin (ED 50 = 128.9 mg/kg) and marginally less potent than ibuprofen (ED 50 = 67.4 mg/kg). The N-hydroxypyridin-2(1 H)one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of chelating 5-LOX iron for exploitation in the design of 5-LOX inhibitory AI drugs.

Synthesis and cyclooxygenase inhibitory activities of linear 1-(methanesulfonylphenyl or benzenesulfonamido)-2-(pyridyl)acetylene regioisomers

A group of 1-(aminosulfonylphenyl and methylsulfonylphenyl)-2-(pyridyl)acetylene regioisomers were designed such that a COX-2 SO 2NH 2 pharmacophore was located at the para-position of the phenyl ring, or a SO 2Me pharmacophore was placed at the ortho-, meta- or para-position of the phenyl ring, on an acetylene template (scaffold). The point of attachment of the pyridyl ring to the acetylene linker was simultaneously varied (2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl) to determine the combined effects of positional, steric, and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. These target linear 1-(phenyl)-2-(pyridyl)acetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction. Structure–activity relationship (SAR) data (IC 50 values) acquired by determination of the in vitro ability of the title compounds to inhibit the COX-1 and COX-2 isozymes showed that the position of the COX-2 SO 2NH 2 or SO 2Me pharmacophore on the phenyl ring, and the point of attachment of the pyridyl ring to the acetylene linker, were either individual, or collective, determinants of COX-2 inhibitory potency and selectivity. A number of compounds discovered in this study, particularly 1-(4-aminosulfonylphenyl)-2-(3-methyl-2-pyridyl)acetylene ( 22), 1-(3-methanesulfonylphenyl)-2-(2-pyridyl)acetylene ( 27), 1-(3-methanesulfonylphenyl)-2-(4-pyridyl)acetylene ( 29), 1-(4-methanesulfonylphenyl)-2-(2-pyridyl)acetylene ( 30), and 1-(4-methanesulfonylphenyl)-2-(3-pyridyl)acetylene ( 31), exhibit potent (IC 50 = 0.04–0.33 μM range) and selective (SI = 18 to >312 range) COX-2 inhibitory activities, that compare favorably with the reference drug celecoxib (COX-2 IC 50 = 0.07 μM; COX-2 SI = 473). The sulfonamide ( 22), and methylsulfonyl ( 27 and 31), compounds exhibited anti-inflammatory activities (ID 50 = 59.9–76.6 mg/kg range) that were intermediate in potency between the reference drugs aspirin (ID 50 = 128.7 mg/kg) and celecoxib (ID 50 = 10.8 mg/kg).