A novel hydrogen-bonding N-oxide–sulfonamide–nitro N—H...O synthon determining the architecture of benzenesulfonamide cocrystals

The structures of novel cocrystals of 4-nitropyridine N-oxide with benzenesulfonamide derivatives, namely, 4-nitrobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C5H4N2O3·C6H6N2O4S, and 4-chlorobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C6H6ClNO2S·C5H4N2O3, are stabilized by N—H...O hydrogen bonds, with the sulfonamide group acting as a proton donor. The O atoms of the N-oxide and nitro groups are acceptors in these interactions. The latter is a double acceptor of bifurcated hydrogen bonds. Previous studies on similar crystal structures indicated competition between these functional groups in the formation of hydrogen bonds, with the priority being for the N-oxide group. In contrast, the present X-ray studies indicate the existence of a hydrogen-bonding synthon including N—H...O(N-oxide) and N—H...O(nitro) bridges. We present here a more detailed analysis of the N-oxide–sulfonamide–nitro N—H...O ternary complex with quantum theory computations and the Quantum Theory of Atoms in Molecules (QTAIM) approach. Both interactions are present in the crystals, but the O atom of the N-oxide group is found to be a more effective proton acceptor in hydrogen bonds, with an interaction energy about twice that of the nitro-group O atoms.

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.

Bifunctional Inhibitors of Influenza Virus Neuraminidase: Molecular Design of a Sulfonamide Linker

The growing resistance of the influenza virus to widely used competitive neuraminidase inhibitors occupying the active site of the enzyme requires the development of bifunctional compounds that can simultaneously interact with other regulatory sites on the protein surface. When developing such an inhibitor and combining structural fragments that could be located in the sialic acid cavity of the active site and the adjacent 430-cavity, it is necessary to select a suitable linker not only for connecting the fragments, but also to ensure effective interactions with the unique arginine triad Arg118-Arg292-Arg371 of neuraminidase. Using molecular modeling, we have demonstrated the usefulness of the sulfonamide group in the linker design and the potential advantage of this functional group over other isosteric analogues.

Antibiotic Resistance in Salmonella Isolated from Ho Chi Minh City (Vietnam) and Difference of Sulfonamide Resistance Gene Existence in Serovars

In this study, a total of 228 raw meat samples (pork: 76, beef: 76, chicken: 76) and 301 raw seafood samples (fish: 199, shrimp: 67, squid: 35) were collected randomly at traditional markets in Ho Chi Minh City (Vietnam). In meat, the ratio of Salmonella spp. was 70.61% (161/228). Among the contaminated meat samples, pork was infected with a ratio of 90.79 % (69/76) while the contamination ratios in beef and chicken were 43.42% (33/76) and 77.63% (59/76), respectively. Salmonella contamination was detected in fish (40.20%), shrimp (7.46%) and squid (17.14%). Because of sulfonamide group is used in Salmonella treatment, the study focused on sulfonamide resistance. In fresh seafood comparison, there were 32.56%, 40% and 10% Salmonella showing resistance to sulfamethoxazol in fish, squid and shrimp, respectively. In fresh meat comparison, there were 31.58%, 16.67% and 55.56% Salmonella showing resistance to sulfamethoxazol in pork, beef and chicken, respectively. Interestingly, there were 21 serovars including 19 identified serovars including S. Kentucky (8), S. Agona (2), S. Infanis (4), S. Saintpaul (1), S. Indiana (1), S. Braenderup (1), S. Potsman (2) and 2 unidentified serovars showing different phenotype to this antibiotic. Among the 21 serovars, only 23.81% strains carried both genes (sul1, sul2). For the sul1 gene, 61.9% strains were presented while sul2 occupied at a lower rate than sul1 with the rate of 52.38%. The study is very interesting and useful to go more functional analysis in sulfonamide resistance.

Palladium-Catalyzed Nondirected Late-Stage C-H Deuteration of Arenes

We describe a palladium catalyzed non-directed late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acyl sulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features an extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labelling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, amongst other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

Identification of non-classical hCA XII inhibitors using combination of computational approaches for drug design and discovery

Human carbonic anhydrase XII (hCA XII) isozyme is of high therapeutic value as a pharmacological target and biomarker for different types of cancer. The hCA XII is one of the crucial effectors that regulates extracellular and intracellular pH and affects cancer cell proliferation, invasion, growth and metastasis. Despite the fact that interaction features of hCAs inhibitors with the catalytic site of the enzyme are well described, lack in the selectivity of the traditional hCA inhibitors based on the sulfonamide group or related motifs is an urgent issue. Moreover, drugs containing sulfanomides can cause sulfa allergies. Thus, identification of novel non-classical inhibitors of hCA XII is of high priority and is currently the subject of a vast field of study. This study was devoted to the identification of novel potential hCA XII inhibitors using comprehensive set of computational approaches for drug design discovery: generation and validation of structure- and ligand-based pharmacophore models, molecular docking, re-scoring of virtual screening results with MMGBSA, molecular dynamics simulations, etc. As the results of the study several compounds with alternative to classical inhibitors chemical scaffolds, in particular one of coumarins derivative, have been identified and are of high interest as potential non-classical hCA XII inhibitors.