Primary Sulfonamides Research Articles

Conversion of Carboxylic Acids to Sulfonamide Bioisosteres via Energy Transfer Photocatalysis.

More than 450 drugs containing a carboxylic acid functional group have been marketed worldwide. Herein, we report a concise and environmentally friendly organic photoinduced protocol for the interconversion of carboxylic acids into their bioisosteres. With this strategy, a variety of substrates, including alkyl, (hetero)aryl, and alkenyl acids, as well as various biologically relevant acids are successfully converted into primary sulfonamides.

From X-ray crystallographic structure to intrinsic thermodynamics of protein-ligand binding using carbonic anhydrase isozymes as a model system.

Carbonic anhydrase (CA) was among the first proteins whose X-ray crystal structure was solved to atomic resolution. CA proteins have essentially the same fold and similar active centers that differ in only several amino acids. Primary sulfonamides are well defined, strong and specific binders of CA. However, minor variations in chemical structure can significantly alter their binding properties. Over 1000 sulfonamides have been designed, synthesized and evaluated to understand the correlations between the structure and thermodynamics of their binding to the human CA isozyme family. Compound binding was determined by several binding assays: fluorescence-based thermal shift assay, stopped-flow enzyme activity inhibition assay, isothermal titration calorimetry and competition assay for enzyme expressed on cancer cell surfaces. All assays have advantages and limitations but are necessary for deeper characterization of these protein-ligand interactions. Here, the concept and importance of intrinsic binding thermodynamics is emphasized and the role of structure-thermodynamics correlations for the novel inhibitors of CA IX is discussed - an isozyme that is overexpressed in solid hypoxic tumors, and thus these inhibitors may serve as anticancer drugs. The abundant structural and thermodynamic data are assembled into the Protein-Ligand Binding Database to understand general protein-ligand recognition principles that could be used in drug discovery.

Palladium-Catalyzed Amino-Sulfonylation of Aryl Iodide Derivatives via the Insertion of Sulfur Dioxide: One-Pot Synthesis of Aryl Primary Sulfonamides with Thiourea Dioxides

AbstractA palladium-catalyzed one-pot amino-sulfonylation of aryl iodide derivatives with thiourea dioxide, PdCl2dppf, and one-pot added hydroxylamine-O-sulfonic acid is presented. This amino-sulfonylation gave structure diversity to aryl primary sulfonamides and features good functional group compatibility, mild reaction conditions, excellent regioselectivity, and moderate to good yields. The robustness and potential of this method have also been successfully demonstrated by late-stage elaboration and gram-scale reaction. This approach achieves the divergent construction of the complex core structures that are prevalent in highly valuable natural products such as Sulpiride, Venetoclax, and Furosemide­.

1,3-Diaryl Triazenes Incorporating Disulfonamides Show Both Antiproliferative Activity and Effective Inhibition of Tumor-associated Carbonic Anhydrases IX and XII.

The aim of this study was to synthesize a library of novel di-sulfa drugs containing 1,3- diaryltriazene derivatives TS (1-13) by conjugation of diazonium salts of primary sulfonamides with sulfa drugs to investigate the cytotoxic effect of these new compounds in different cancer types and to determine their inhibitory activity against tumor-associated carbonic anhydrases IX and XII. A carbonic anhydrase inhibitory activity of the obtained compounds was evaluated against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII) by a stoppedflow CO2 hydrase assay. In addition, in vitro, cytotoxicity studies were applied by using A549 (lung cancer), BEAS-2B (normal lung), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), CRL-4010 (normal breast epithelium), HT-29 (colon cancer), and HCT -116 (colon cancer) cell lines. As a result of the inhibition data, the 4-aminobenzenesulfonamide derivatives were more active than their 3-aminobenzenesulfonamide counterparts. More specifically, compounds TS-1 and TS-2, both of which have primary sulfonamides on both sides of the triazene linker, showed the best inhibitory activity against hCA IX with Ki values of 19.5 and 13.7 nM and also against hCA XII with Ki values of 6.6 and 8.3 nM, respectively. In addition, in vitro cytotoxic activity on the human breast cancer cell line MCF-7 showed that some derivatives of di-sulfa triazenes, such as TS-5 and TS-13, were more active than SLC-0111. With the aim of developing more potent and isoform-selective CA inhibitors, these novel hybrid molecules containing sulfa drugs, triazene linkers, and the classical primary sulfonamide chemotype may be considered an interesting example of effective enzyme inhibitors and important anticancer agents.

Merging Cobalt-Catalyzed C-H Activation with the Mannich Reaction: A Modular Approach to α-Substituted N-Sulfonyl Amines.

A three-component synthesis of α-substituted N-sulfonyl amines from aryl aldehydes, primary sulfonamides, and (hetero)arenes is described. This transformation enables a straightforward and modular synthesis of highly substituted sulfonamide scaffolds in good yields. The direct functionalization of C(sp2)-H bonds via cobalt-catalyzed C-H-activation offers an appealing and atom-economical alternative to classical methods for the synthesis of α-arylated amines such as the Petasis or Mannich-type reactions.

Synthesis, molecular docking analysis, drug-likeness evaluation, and inhibition potency of new pyrazole-3,4-dicarboxamides incorporating sulfonamide moiety as carbonic anhydrase inhibitors.

A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441 µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms.

Catalytic three-component carboamination of unactivated alkenes with primary sulfonamides

We demonstrate a catalytic radical three-component reaction using primary sulfonamides as N–H precursors, which provides a novel method for constructing a library of complex architectures through carbon–nitrogen and carbon–carbon bond formation.

Electrochemical remote C(sp3)–H thiocyanation

An electrochemical thiocyanation of distal C(sp3)–H bonds based on amidyl radical-mediated 1,5-HAT has been developed. The transformation is highly site-selective and compatible with primary, secondary, and tertiary sulfonamides, and bioactive derivatives.

Diazotization-Enabled Deaminative Late-Stage Functionalization of Primary Sulfonamides.

We, for the first time, disclosed a simple and efficient strategy for the late-stage functionalization of primary sulfonamides by diazotization, leading to sulfonyl chlorides, sulfonates, and complex sulfonamides. This protocol obviates the requirement for the prefunctionalization of sulfonamides. Its applicability is exemplified by the late-stage functionalization of sulfonamide-type drugs.

Novel and Predictive QSAR Model and Molecular Docking: New Natural Sulfonamides of Potential Concern against SARS-Cov-2

Background: Since the outbreak of the COVID-19 pandemic in 2019, the world has been racing to develop effective drugs for treating this deadly disease. Although there are now some vac-cines that have somewhat alleviated global panic, the lack of approved drugs remains a persistent challenge. Consequently, there is a pressing need to discover new therapeutic molecules. Methods: In this study, we explore the application of a quantitative structure−activity relationship (QSAR) model to predict the efficacy of 28 cyclic sulfonamide derivatives against SARS-CoV-2. The model was developed using multiple linear regression, and six molecular descriptors were identified as the most significant factors in determining the inhibitory activity. This proposed QSAR model holds the potential for aiding the virtual screening and drug design process in the development of new and more effective SARS-CoV-2 inhibitors. The model was also applied to seven natural products primary sulfonamides and sulfamates, demonstrating promising activity Results: The study results indicated that the atom count, as represented by the descriptor nCl, had the most significant impact on the inhibitory activity against SARS-CoV-2. The proposed model was val-idated using various statistical parameters, confirming its validity, robustness, and predictiveness, with a high correlation coefficient (R2) of 0.77 for the training group and 0.95 for the test group. Further-more, we predicted the activity of seven natural compounds, and among them, Dealanylascamycin exhibited the highest predicted activity. Subsequently, Dealanylascamycin was docked to SARS-CoV-2 and the results of the docking study further strengthened its potential as a promising candidate against COVID-19, suggesting that it should be considered for further optimization and validation. Conclusion: Our findings demonstrate promising predicted inhibitory activity against SARS-CoV-2 for seven natural products, primary sulfonamides, and primary sulfamates.

Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors

Considering the unrecognised physio-pathological role of human carbonic anhydrase III (hCA III), a structure-based drug design was set up to identify the first-in-class potent and selective inhibitors of this neglected isoform. hCA III targeting was planned considering a unique feature of its active site among the other hCA isoforms, i.e. the Leu198/Phe198 substitution which interferes with the binding of aromatic/heterocyclic sulfonamides and other inhibitors. Thus, new aliphatic primary sulfonamides possessing long and flexible (CH2)nSO2NH2 moieties were designed to coordinate the zinc(II) ion, bypassing the bulky Phe198 residue. They incorporate 1,2,3-triazole linkers which connect the tail moieties to the sulfonamide head, enhancing thus the contacts at the active site entrance. Some of these compounds act as nanomolar and selective inhibitors of hCA III over other isoforms. Docking/molecular dynamics simulations were used to investigate ligand/target interactions for these sulfonamides which might improve our understanding of the physio-pathological roles of hCA III.

Versatile Diazomethane Sulfonamide for Expedited Exploration of Azole-Based Carbonic Anhydrase Inhibitors via [3+2] Cycloaddition.

A newly introduced diazo reagent, 1-diazo-N,N-bis(4-methoxybenzyl)methanesulfonamide, enables access to a range of azole-based primary sulfonamides via [3+2] cycloaddition followed by protecting group removal. Such compounds are representative of the sulfonamide chemical space highly relevant but hitherto not investigated in the context of inhibition of therapeutically relevant isoforms of carbonic anhydrase enzyme. Using this reagent, three sets of primary sulfonamides based on pyrazole, 1,2,3-triazole and tetrazole cores were synthesized and profiled for inhibition of tumor-associated hCA IX and XII isoforms as well as abundant cytosolic hCA I and II isoforms. Using virtual library design and docking prioritization tool of the Schrödinger suite, one of the promising leads was evolved into a dual hCA IX/XII inhibitor with excellent selectivity over off-target hCA I and II. The new synthetic strategy to access azole-based primary sulfonamides will support the discovery of novel, isoform-selective inhibitors of carbonic anhydrase within the poorly explored azole chemical space.

Iron-Catalyzed Oxidative α-Amination of Ketones with Primary and Secondary Sulfonamides.

We report the iron-catalyzed α-amination of ketones with sulfonamides. Using an oxidative coupling approach, ketones can be directly coupled with free sulfonamides, without the need for prefunctionalization of either substrate. Primary and secondary sulfonamides are both competent coupling partners, with yields from 55% to 88% for deoxybenzoin-derived substrates.

Synthesis of N-Acylsulfenamides from Amides and N-Thiosuccinimides.

Herein is reported a robust and general method for the preparation of N-acylsulfenamides, important functionalities that have recently been utilized as central inputs for the asymmetric synthesis of high oxidation state sulfur compounds. This straightforward transformation proceeds by reaction of primary amides, carbamates, sulfonamides, sulfinamides, and ureas with stable N-thiosuccinimides or N-thiophthalimides, which in turn are prepared in a single step from commercial thiols. The use of stable N-thiosuccinimide and N-thiophthalimide reactants is desirable because it obviates the use of highly reactive sulfenyl chlorides.

Quantum Chemical Prediction of the Acidities of Sulfonamide Inhibitors of Carbonic Anhydrase.

This study examined two pKa calculation approaches (direct and proton exchange schemes) that employ high-level quantum chemical methods and implicit solvent models to predict aqueous Brønsted acidities of a large set of sulfonamides. For gas-phase deprotonation energies, the DSD-PBEP86-D3(BJ) double-hybrid functional provided the best agreement with the LNO-CCSD(T)/CBS benchmark with a mean absolute deviation less than 2 kJ mol-1 when the aug-cc-pVTZ or larger basis sets are used. For a large test set of 54 primary and secondary sulfonamides, the use of the DSD-PBEP86-D3(BJ)/aug-cc-pVTZ level of theory in conjunction with SM12 solvation free energies predict their pKa values with a mean accuracy of 0.9 units. In comparison, the SMD and ADF-COSMO-RS models have slightly higher mean errors of 1.4 and 1.1 pKa units provided that the proton exchange scheme was employed to cancel the systematic errors in these models. The performance of these protocols was less ideal when applied to sulfonic acids, sulfamates, and N-substituted sulfonamides, indicating that the degree of error cancellation is sensitive to the chemical environment around the -NH2 head group. The validated protocols were then used to estimate the pKa values of arylsulfonamide carbonic anhydrase inhibitors, which are used to correct their experimentally measured binding free energies to account for deprotonation of the sulfonamide group upon binding to the enzyme. These corrected values did not have a significant impact on the correlation with MMGBSA binding free energies obtained from classical MD simulations where the ligand is usually considered in the deprotonated form.

Role of ammonia-oxidizing microorganisms in the removal of organic micropollutants during simulated riverbank filtration

Biodegradation plays an important role in the removal of organic micropollutants (OMPs) during riverbank filtration (RBF) for drinking water production. The ability of ammonia-oxidizing microorganisms (AOM) to remove OMPs has attracted increasing attention. However, the distribution of AOM in RBF and its role in the degradation of OMPs remains unknown. In this study, the behavior of 128 selected OMPs and the distribution of AOM and their roles in the degradation of OMPs in RBF were explored by column and batch experiments simulating the first meter of the riverbank. The results showed that the selected OMPs were effectively removed (82/128 OMPs, >70% removal) primarily by biodegradation and partly by adsorption. Inefficiently removed OMPs tended to have low molecular weights, low log P, and contain secondary amides, secondary sulfonamides, secondary ketimines, and benzyls. In terms of the microbial communities, the relative abundance of AOM increased from 0.1%–0.2% (inlet-sand) to 5.3%–5.9% (outlet-sand), which was dominated by ammonia-oxidizing archaea whose relative abundance increased from 23%–72% (inlet-sand) to 97% (outlet-sand). Comammox accounted for 23%–64% in the inlet-sand and 1% in the outlet-sand. The abundances of AOM amoA genes kept stable in the inlet-sand of control columns, while decreased by 78% in the treatment columns, suggesting the inhibition effect of allylthiourea (ATU) on AOM. It is observed that AOM played an important role in the degradation of OMPs, where its inhibition led to the corresponding inhibition of 32 OMPs (5/32 were completely suppressed). In particular, OMPs with low molecular weights and containing primary amides, secondary amides, benzyls, and secondary sulfonamides were more likely to be removed by AOM. This study reveals the vital role of AOM in the removal of OMPs, deepens our understanding of the degradation of OMPs in RBF, and offers valuable insights into the physiochemical properties of OMPs and their AOM co-metabolic potential.

Cu‐Catalyzed Coupling Reactions of Sulfonamides with (Hetero)Aryl Chlorides/Bromides

AbstractDirectN‐arylation of sulfonamides is a very attractive approach for preparing pharmaceutically importantN‐(hetero)aryl sulfonamides because it avoids the potential genotoxic problem resulting from the previous condensation method. Most known catalytic methods suffer from limited reaction scope and inconveniency on metal catalyst and ligand availability. Here we described that the combination of copper and oxalamides (or 4‐hydroxypicolinamides) offers a powerful catalytic system forN‐arylation of sulfonamides. A wide range of primary and secondary sulfonamides were able to couple with a series of (hetero)aryl bromides in the presence of 2–5 mol % copper salts and oxalamides at 100 °C. Coupling of primary sulfonamides with (hetero)aryl chlorides worked well under the catalysis of Cu2O and a 4‐hydroxypicolinamide. The catalytic method enabled direct sulfonamidation of four chloro‐containing marketed drugs and preparation of two sulfonamide drugs from the corresponding aryl halides.

One-Pot Synthesis of Diaryl Sulfonamides using an Iron- and Copper-Catalyzed Aryl C–H Amidation Process

AbstractA one-pot, two-stage synthesis of diaryl sulfonamides using sequential iron and copper catalysis is developed. Regioselective para-iodination of activated arenes by the super Lewis acid, iron triflimide and N-iodosuccinimide (NIS), is followed by a copper(I)-catalyzed N-arylation reaction. The process is found to be applicable for the coupling of a range of anisoles, anilines and acetanilides with primary sulfonamides and is used for the one-pot synthesis of biologically important compounds.

Late-stage sulfonic acid/sulfonate formation from sulfonamides via sulfonyl pyrroles

Sulfonamides are present in a range of useful molecules, such as drugs and agrochemicals. In recent years, the functionalization of sulfonamides via S–N bond cleavage has received increased attention. In this report, we detail an accessible and low-cost route for transforming primary sulfonamides into the corresponding sulfonic acids/sulfonates via sulfonyl pyrroles. The reaction is demonstrated with a range of substrates including aryl and alkyl sulfonamides, and in the late-stage functionalization of several sulfonamide-containing drug molecules.

Design, synthesis, SAR, and biological evaluation of saccharin-based hybrids as carbonic anhydrase inhibitors.

Saccharin is a cyclic secondary sulfonamide, which is a selective inhibitor of the tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) enzymes CA IX and CA XII compared to many primary sulfonamides. In this study, new saccharin-1,2,3-triazole and saccharin-1,2,4-oxadiazole hybrids were synthesized. All the newly synthesized molecules were screened for their CA-inhibitory activity against four important human CA (hCA) isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds 8a and 8f emerged as potent hCA II inhibitors (Ki = 3 µM). Compounds 6d, 6e and 7a, 7b were highly selective against hCA IX (6d, 6e) and hCA II (7a, 7b), with moderate inhibitory activity. The activity of these compounds was further confirmed by performing in silico docking studies against hCA II and hCA IX.