Acyl Sulfonamide Research Articles

Recognition Properties of Carboxylic Acid Bioisosteres: Anion Binding by Tetrazoles, Aryl Sulfonamides, and Acyl Sulfonamides on a Calix[4]arene Scaffold

Tetrazoles and acyl sulfonamides are functional groups that are common in medicinal chemistry but virtually unexplored as recognition elements in supramolecular chemistry. We report here on the anion binding properties of these highly acidic N-H functional groups. We have prepared two new calixarene-based tetrazole-containing hosts, as well as new acetyl sulfonamide and benzoyl sulfonamide hosts. We also report on analogous hosts bearing the better-known aryl sulfonamide functional group as a point of comparison. We find that these hosts are competent anion binders and that the recognition of anions by these groups is highly dependent on their conformational preferences. We also report in detail on the preferred molecular shape of each acid bioisostere as determined by calculations and structural database surveys, and discuss how these shapes impact binding in the context of the reported hosts.

Application of Fragment Growing and Fragment Linking to the Discovery of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase

Two distinct strategies uncovered potent inhibitors of the title enzyme. X-ray crystallography and isothermal titration calorimetry guided the systematic elaboration of fragments identified from biophysical screens. The excellent inhibitor shown in the enzyme active site on the right was formed by connection of the lead fragments (left) with an acyl sulfonamide linker and resembles the best inhibitor discovered by the fragment-growing strategy.

Candidate Biomarkers of Response to an Experimental Cancer Drug Identified through a Large-scale RNA Interference Genetic Screen

A major impediment in the optimal selection of cancer patients for the most effective therapy is the lack of suitable biomarkers that foretell the response of a patient to a given drug. In the present study, we have used large-scale RNA interference-based genetic screens to find candidate biomarkers of resistance to a new acyl sulfonamide derivative, R3200. This compound inhibits the proliferation of tumor cells in vitro and in vivo, but its mechanism of action is unknown. We used a large-scale RNA interference genetic screen to identify modulators of the efficacy of R3200. We searched for genes whose suppression in an in vitro cell system could cause resistance to the anticancer effects of R3200. We report here that knockdown of either RBX1 or DDB1 causes resistance to the anticancer effects of R3200, raising the possibility that these two genes may have utility as biomarkers of response to this drug in a clinical setting. Interestingly, both RBX1 and DDB1 are part of an E3 ubiquitin ligase complex. We propose that suppression of the activity of a RBX1 and DDB1-containing E3 ligase complex leads to the stabilization of certain proteins, the increased abundance of which is in turn responsible for resistance to R3200. Moreover, our data suggest that RBX1 and DDB1 could potentially be developed into biomarkers of resistance to acyl sulfonamide-based cancer drugs. This will require clinical validation in a series of patients treated with R3200.

Preparation of N-(α,β-unsaturated acyl)-sulfonamides

N-(α,β-Unsaturated acyl)sulfonamides are prepared (i) by the N-acylation of sulfonamides with N-(α,β-unsaturated acyl)benzotriazoles in the presence of potassium tert-butoxide or sodium hydride and (ii) by reactions of appropriate α,β-unsaturated carboxamides with sulfonylbenzotriazoles in the presence of sodium hydride. Published preparations of N-(α,β-unsaturated acyl)sulfonamides include (i) the acylation of sulfonamides (RSO2NH2) by (a) unsaturated acyl chlorides (R'CH=CHCOCl) in the presence of a base (such as triethylamine, 3,5a n-butyllithium, 4d or NaH 6,7 ) or a copper powder catalyst; 8 (b) unsaturated carboxylic acids via mixed anhydride in the presence of Lewis acid catalyst; 9 (ii) reactions of aryl isocyanates (RSO2NCO) with 1-alkenyltrialkylstannanes, di-1- alkenyldibutylstannanes in the presence of aluminium trichloride 10a or with substituted alkenes; 10b (iii) reactions of sulfonamide with the Wittig adduct obtained from (triphenylphosphoranylidene)ketene and an aldehyde; 11 (iv) coupling of unsaturated acids with sulfonamides in the presence of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI); 2,3,12 (v) dehydrogenation of the corresponding saturated analogs by using LDA followed by N-tert- butylbenzenesulfinimidoyl chloride. 5a,13 Herein, we report the acylation of sulfonamides with stable, crystalline N-(α,β-unsaturated acyl)benzotriazoles to give N-(α,β-unsaturated acyl)sulfonamides.

Sulfonamides of homoproline and dipeptides as organocatalysts for Michael and aldol reactions

Sulfonamides of the non-natural amino acid homoproline and the dipeptide Pro–Phe were synthesised and evaluated for their catalytic activity in Michael and aldol reactions. Sulfonamides of homoproline outperform proline and Pro–Phe in the Michael reaction, whereas sulfonamides of Pro–Phe lead to better results in the aldol reaction. The results of the present study show that the conversion of the carboxylic group of either homoproline or dipeptide Pro–Phe to the bioisosteric acyl sulfonamide group lead to improved organocatalysts.

Synthesis of 2‐oxoamides based on sulfonamide analogs of γ‐amino acids and their activity on phospholipase A2

A variety of lipophilic 2-oxoamides containing sulfonamide analogs of gamma-amino acids as well as acyl sulfonamides of gamma-aminobutyric acid were synthesized. Their ability to inhibit intracellular GIVA cPLA2 and GVIA iPLA2 as well as secreted GV sPLA2 was evaluated. The sulfonamide group seems a bioisosteric group suitable to replace the carboxyl group in 2-oxoamide inhibitors of GVIA cPLA2.

Carboxylic acid isosteres improve the activity of ring-fused 2-pyridones that inhibit pilus biogenesis in E. coli

Ring-fused 2-pyridones, termed pilicides, are small synthetic compounds that inhibit pilus assembly in uropathogenic Escherichia coli. Their biological activity is clearly dependent upon a carboxylic acid functionality. Here, we present the synthesis and biological evaluation of carboxylic acid isosteres, including, for example, tetrazoles, acyl sulfonamides, and hydroxamic acids of two lead 2-pyridones. Two independent biological evaluations show that acyl sulfonamides and tetrazoles significantly improve pilicide activity against uropathogenic E. coli.

Potent triazolyl-proline-based inhibitors of HCV NS3 protease

The design and synthesis of tripeptide-based inhibitors of the HCV NS3 protease containing a novel P2-triazole is described. Replacement of the P2 quinoline with a triazole moiety provided a versatile handle which could be expediently modified to generate a diverse series of inhibitors. Further refinement by the incorporation of an aryl-substituted triazole and replacement of the P1 acid with an acyl sulfonamide ultimately provided inhibitors with interesting cellular activity.

β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors

In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of α- and β-amino acids has been synthesized. To understand the structural implications of β-amino acid substitution, the P 1, P 2, and P 3 positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the α-peptide analogues. However, several compounds exhibited μM potency. Inhibition data were compared with modeled ligand–protein binding poses to understand how changes in ligand structure affected inhibition potency. The P 3 position seemed to be the least sensitive position for β-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q 2 = 0.48 and r pred 2 = 0.68 .

Evaluation of a diverse set of potential P 1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors

There is an urgent need for more efficient therapies for people infected with hepatitis C virus (HCV). HCV NS3 protease inhibitors have shown proof-of-concept in clinical trials, which make the virally encoded NS3 protease an attractive drug target. Product-based NS3 protease inhibitors comprising a P 1 C-terminal carboxylic acid have shown to be effective and we were interested in finding alternatives to this crucial carboxylic acid group. Thus, a series of diverse P 1 functional groups with different acidity and with possibilities to form a similar, or an even more powerful, hydrogen bond network as compared to the carboxylic acid were synthesized and incorporated into potential inhibitors of the NS3 protease. Biochemical evaluation of the inhibitors was performed in both enzyme and cell-based assays. Several non-acidic C-terminal groups, such as amides and hydrazides, were evaluated but failed to produce inhibitors more potent than the corresponding carboxylic acid inhibitor. The tetrazole moiety, although of similar acidity to a carboxylic acid, provided an inhibitor with mediocre potencies in both assays. However, the acyl cyanamide and the acyl sulfinamide groups rendered compounds with low nanomolar inhibitory potencies and were more potent than the corresponding carboxylic acid inhibitor in the enzymatic assay. Additionally, results from a pH-study suggest that the P 1 C-terminal of the inhibitors comprising a carboxylic acid, an acyl sulfonamide or an acyl cyanamide group binds in a similar mode in the active site of the NS3 protease.

Facile preparation of N-acylsulfonamides by using sulfonyl isocyanate

N-Acylsulfonamide is widely used as a carboxylic acid bioisostere. A rapid and mild acyl sulfonamide preparation methodology from carboxylic acid and arylsulfonyl isocyanate in the presence of amine is described. The preparation of biologically active acylsulfonamide by our methodology is also presented.

Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors

Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1–P3 cyclization, which gave products with inhibition constants in the nanomolar range (∼75 nM).

Exploration of acyl sulfonamides as carboxylic acid replacements in protease inhibitors of the hepatitis C virus full-length NS3

The hepatitis C virus (HCV) NS3 protease has emerged as a promising anti-HCV drug target. Herein, we present an investigation of NS3 inhibitors comprising the acyl sulfonamide functionality. A series of tetra- and tripeptide based acyl sulfonamide inhibitors and their structure–activity relationships from both enzymatic and cell-based in vitro assays are presented. In summary, the acidity of the acyl sulfonamide functionality, the character of the P1 side chain, and the acyl sulfonamide substituent were found to be important for the inhibitory potencies.

Easy‐to‐Execute Carbonylations: Microwave Synthesis of Acyl Sulfonamides Using Mo(CO)6 as a Solid Carbon Monoxide Source.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly Efficient Coupling of β‐Substituted Aminoethane Sulfonyl Azides with Thio Acids, Toward a New Chemical Ligation Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Easy-to-Execute Carbonylations: Microwave Synthesis of Acyl Sulfonamides Using Mo(CO)6 as a Solid Carbon Monoxide Source

The development of a robust palladium-catalyzed amidocarbonylation protocol for the preparation of aromatic acyl sulfonamides utilizing high-density microwave heating is described. This synthetic approach employs Mo(CO)(6) as a convenient CO-releasing reagent and allows for the direct preparation of acyl sulfonamides from both aryl iodides and aryl bromides. The reactions can be performed under air, employing only 15 min of microwave irradiation, to produce acyl sulfonamide derivatives in good to excellent yields. To illustrate the usefulness of this method, we reported the synthesis of a novel hepatitis C virus NS3 protease inhibitor.

Highly Efficient Coupling of β-Substituted Aminoethane Sulfonyl Azides with Thio Acids, toward a New Chemical Ligation Reaction

[reaction: see text] A highly efficient coupling of protected beta-substituted aminoethane sulfonyl azides with thio acids is reported. In the case of peptide thio acids, this method encompasses a new chemoselective ligation method. Furthermore, the resulting alpha-amino acyl sulfonamides can be alkylated with suitable electrophiles to obtain densely functionalized sulfonamide scaffolds.

Acyl sulfonamide anti-proliferatives. Part 2: Activity of heterocyclic sulfonamide derivatives

The anti-proliferative activity of acylated heterocyclic sulfonamides is described in Vascular Endothelial Growth Factor-dependent Human Umbilical Vascular Endothelial Cells (VEGF-HUVEC) and in HCT116 tumor cells in a soft agar diffusion assay.

A Facile Cleavage of the Carbon‐Nitrogen Bond of Aromatic Imines Using Acylation Reagents in the Presence of Catalytic Amounts of Ytterbium Triflate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Structure-activity relationships for the selectivity of hepatitis C virus NS3 protease inhibitors.

The selectivity of hepatitis C virus (HCV) non-structural protein 3 (NS3) protease inhibitors was determined by evaluating their inhibitory effect on other serine proteases (human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), bovine pancreatic chymotrypsin (BPC)) and a cysteine protease (cathepsin B). For these peptide inhibitors, the P1-side chain and the C-terminal group were the major determinants of selectivity. Inhibitors with electrophilic C-terminal residues were generally non-selective while compounds with non-electrophilic C-terminal residues were more selective. Furthermore, compounds with P1 aminobutyric acid residues were non-selective, while 1-aminocyclopropane-1-carboxylic acid (ACPC) and norvaline-based inhibitors were generally selective. The most potent and selective inhibitors of NS3 protease tested contained a non-electrophilic phenyl acyl sulfonamide C-terminal residue. HLE was most likely to be inhibited by the HCV protease inhibitors, in agreement with similar substrate specificities for these enzymes. The identified structure-activity relationships for selectivity are of significance for design of selective HCV NS3 protease inhibitors.