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Nitro Sulfonyl Fluorides are a new pharmacophore for the development of antibiotics.

ABSTRACT: The development of antibiotics against Gram-negative bacteria is a central problem in drug discovery. In this report, we demonstrate that aromatic sulfonyl fluorides with a nitro group in their ortho position have remarkable antibacterial activity and are active against drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), multidrug resistant Acinetobacter baumannii, and Pseudomonas aeruginosa.

SUBMITTER: Sadlowski C

PROVIDER: S-EPMC6366622 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Nitro Sulfonyl Fluorides are a new pharmacophore for the development of antibiotics.

Sadlowski Corinne C Park Bora B Araújo Clarissa C Das Subhamoy S Kerr D Lucas DL He Maomao M Han Hesong H Riley Lee L Murthy Niren N

Molecular systems design & engineering 20180607 4

The development of antibiotics against Gram-negative bacteria is a central problem in drug discovery. In this report, we demonstrate that aromatic sulfonyl fluorides with a nitro group in their ortho position have remarkable antibacterial activity and are active against drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), multidrug resistant Acinetobacter baumannii, and Pseudomonas aeruginosa. ...[more]

PMID: 30740245

Similar Datasets

A rapid access to aliphatic sulfonyl fluorides.

Project description:The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO2F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.

| S-EPMC6704106 | biostudies-literature

Broad-spectrum antimalarial activity of peptido sulfonyl fluorides, a new class of proteasome inhibitors.

Project description:Despite declining numbers of cases and deaths, malaria remains a major public health problem in many parts of the world. Today, case management relies heavily on a single class of antimalarial compounds: artemisinins. Hence, development of resistance against artemisinins may destroy current malaria control strategies. Beyond malaria control are elimination and eradication programs that will require drugs with good activity against acute infection but also with preventive and transmission-blocking properties. Consequently, new antimalarials are needed not only to ensure malaria control but also for elimination and eradication efforts. In this study, we introduce peptido sulfonyl fluorides (PSF) as a new class of compounds with antiplasmodial activity. We show that PSF target the plasmodial proteasome and act on all asexual stages of the intraerythrocytic cycle and on gametocytes. PSF showed activities at concentrations as low as 20 nM against multidrug-resistant and chloroquine-sensitive Plasmodium falciparum laboratory strains and clinical isolates from Gabon. Structural requirements for activity were identified, and cytotoxicity in human HeLa or HEK 293 cells was low. The lead PSF PW28 suppressed growth of Plasmodium berghei in vivo but showed signs of toxicity in mice. Considering their modular structure and broad spectrum of activity against different stages of the plasmodial life cycle, proteasome inhibitors based on PSF have a great potential for further development as preclinical candidate compounds with improved species-specific activity and less toxicity.

| S-EPMC3719782 | biostudies-literature

Sulfonyl fluorides as privileged warheads in chemical biology.

Project description:Sulfonyl fluoride electrophiles have found significant utility as reactive probes in chemical biology and molecular pharmacology. As warheads they possess the right balance of biocompatibility (including aqueous stability) and protein reactivity. Their functionality is privileged in this regard as they are known to modify not only reactive serines (resulting in their common use as protease inhibitors), but also context-specific threonine, lysine, tyrosine, cysteine and histidine residues. This review describes the application of sulfonyl fluoride probes across various areas of research and explores new approaches that could further enhance the chemical biology toolkit. We believe that sulfonyl fluoride probes will find greater utility in areas such as covalent enzyme inhibition, target identification and validation, and the mapping of enzyme binding sites, substrates and protein-protein interactions.

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Rh-Catalyzed Highly Enantioselective Synthesis of Aliphatic Sulfonyl Fluorides.

Project description:Rh-catalyzed, highly enantioselective (up to 99.8% ee) synthesis of aliphatic sulfonyl fluorides was accomplished. This protocol provides a portal to a class of novel 2-aryl substituted chiral sulfonyl fluorides, which are otherwise extremely difficult to access. This asymmetric synthesis has the feature of mild conditions, excellent functional group compatibility, and wide substrate scope (51 examples) generating a wide array of structurally unique chiral ?-arylated sulfonyl fluorides for sulfur(VI) fluoride exchange (SuFEx) click reaction and drug discovery.

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One-pot palladium-catalyzed synthesis of sulfonyl fluorides from aryl bromides.

Project description:A mild, efficient synthesis of sulfonyl fluorides from aryl and heteroaryl bromides utilizing palladium catalysis is described. The process involves the initial palladium-catalyzed sulfonylation of aryl bromides using DABSO as an SO2 source, followed by in situ treatment of the resultant sulfinate with the electrophilic fluorine source NFSI. This sequence represents the first general method for the sulfonylation of aryl bromides, and offers a practical, one-pot alternative to previously described syntheses of sulfonyl fluorides, allowing rapid access to these biologically important molecules. Excellent functional group tolerance is demonstrated, with the transformation successfully achieved on a number of active pharmaceutical ingredients, and their precursors. The preparation of peptide-derived sulfonyl fluorides is also demonstrated.

| S-EPMC5369543 | biostudies-literature

N-(2-Amino-phenyl-sulfonyl)-N-(2-nitro-phenyl-sulfonyl)methylamine.

Project description:In the title mol-ecule, C(13)H(13)N(3)O(6)S(2), the two benzene rings form a dihedral angle of 28.59?(7)°. The crystal sructure exhibits weak inter-molecular N-H?O, C-H?O and C-H?N hydrogen bonds and ?-? inter-actions [centroid-to-centroid distance = 3.899?(3)?Å].

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Methyl 4-methyl-sulfonyl-2-nitro-benzoate.

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Organocatalyzed Trifluoromethylation of Ketones and Sulfonyl Fluorides by Fluoroform under a Superbase System.

Project description:Fluoroform (HCF3, HFC-23) is a side product in the manufacture of polytetrafluoroethylene (Teflon). Despite its attractive properties, taming HCF3 for trifluoromethylation is quite problematic owing to its low acidity and the lability of the naked trifluoromethyl carbanion generated from HCF3. Herein we report the organic-superbase-catalyzed trifluoromethylation of ketones and arylsulfonyl fluorides by HCF3. The reactions were carried out by using a newly developed "superbase organocatalyst system" consisting of catalytic amounts of P4-tBu and N(SiMe3)3. A series of aryl and alkyl ketones were converted into the corresponding ?-trifluoromethyl carbinols in good yields under the organocatalysis conditions in THF. The superbase organocatalytic system can also be applied to the trifluoromethylation of arylsulfonyl fluorides for biologically important aryl triflones in THF or DMF in good yields. Protonated P4-tBu, H[P4-tBu](+), is suggested to be crucial for the catalytic process. This new catalytic methodology using HCF3 is expected to expand the range of synthetic applications of trifluoromethylation.

| S-EPMC4608523 | biostudies-literature

Redox-Neutral Organometallic Elementary Steps at Bismuth: Catalytic Synthesis of Aryl Sulfonyl Fluorides.

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| S-EPMC8719321 | biostudies-literature

Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate.

Project description:Molecules that bind selectively to a given protein and then undergo a rapid chemoselective reaction to form a covalent conjugate have utility in drug development. Herein a library of 1,3,4-oxadiazoles substituted at the 2 position with an aryl sulfonyl fluoride and at the 5 position with a substituted aryl known to have high affinity for the inner thyroxine binding subsite of transthyretin (TTR) was conceived of by structure-based design principles and was chemically synthesized. When bound in the thyroxine binding site, most of the aryl sulfonyl fluorides react rapidly and chemoselectively with the pKa-perturbed K15 residue, kinetically stabilizing TTR and thus preventing amyloid fibril formation, known to cause polyneuropathy. Conjugation t50s range from 1 to 4 min, ~1400 times faster than the hydrolysis reaction outside the thyroxine binding site. X-ray crystallography confirms the anticipated binding orientation and sheds light on the sulfonyl fluoride activation leading to the sulfonamide linkage to TTR. A few of the aryl sulfonyl fluorides efficiently form conjugates with TTR in plasma. Eleven of the TTR covalent kinetic stabilizers synthesized exhibit fluorescence upon conjugation and therefore could have imaging applications as a consequence of the environment sensitive fluorescence of the chromophore.

| S-EPMC3630275 | biostudies-literature

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