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1.
Bioorg Med Chem ; 27(20): 115050, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31474471

ABSTRACT

C4-phenylthio ß-lactams are a new family of antibacterial agents that have activity against two phylogenetically distant bacteria - Mycobacterium tuberculosis (Mtb) and Moraxella catarrhalis (M. cat). These compounds are effective against ß-lactamase producing Mtb and M. cat unlike the clinically relevant ß-lactam antibiotics. The structure-activity relationship for the C4 phenylthio ß-lactams has not yet been completely defined. Earlier efforts in our laboratories established that the C4-phenylthio substituent is essential for antimicrobial activity, while the N1 carbamyl substituent plays a more subtle role. In this present study, we investigated the role that the stereochemistry at C4 plays in these compounds' antibacterial activity. This was achieved by synthesizing and testing the antimicrobial activity of diastereomers with a chiral carbamyl group at N1. Our findings indicate that a strict stereochemistry for the C4-phenylthio ß-lactams is not required to obtain optimal anti-Mtb and anti-M. cat activity. Furthermore, the structure-bioactivity profiles more closely relate to the electronic requirement of the phenylthiogroup. In addition, the MICs of Mtb are sensitive to growth medium composition. Select compounds showed activity against non-replicating and multi-drug resistant Mtb.


Subject(s)
Anti-Bacterial Agents/pharmacology , Moraxella catarrhalis/drug effects , Mycobacterium tuberculosis/drug effects , Sulfhydryl Compounds/pharmacology , beta-Lactams/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Resistance, Bacterial/drug effects , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Moraxella catarrhalis/growth & development , Mycobacterium tuberculosis/growth & development , Structure-Activity Relationship , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/chemistry , beta-Lactams/chemical synthesis , beta-Lactams/chemistry
2.
Org Lett ; 21(10): 3674-3677, 2019 05 17.
Article in English | MEDLINE | ID: mdl-31021647

ABSTRACT

The synthesis of the hexasaccharide fragment of landomycin A is reported. Using p-toluenesulfonyl chloride mediated dehydrative glycosylation, we constructed the deoxy-sugar linkages in a stereoselective fashion without the need for temporary prosthetic groups to control selectivity. Through this approach, the hexasaccharide was obtained in 28 steps and 8.9% overall yield, which is an order of magnitude higher than that of previously reported approaches.


Subject(s)
Aminoglycosides/chemical synthesis , Oligosaccharides/chemical synthesis , Aminoglycosides/chemistry , Glycosylation , Molecular Structure
3.
Chemistry ; 24(30): 7610-7614, 2018 May 28.
Article in English | MEDLINE | ID: mdl-29572995

ABSTRACT

A next-generation reagent-controlled approach for the synthesis of 2,6-dideoxy and 2,3,6-trideoxy sugar donors in good yield and high ß-selectivity is reported. The use of p-toluenesulfonyl chloride and potassium hexamethyldisilazide (KHMDS) greatly simplifies deoxy-sugar glycoside construction, and can be used for gram-scale glycosylation reactions. The development of this approach and its application to the construction of ß-linked deoxy-sugar oligosaccharides are described.


Subject(s)
Carbohydrates/chemical synthesis , Deoxy Sugars/chemical synthesis , Oligosaccharides/chemical synthesis , Carbohydrates/chemistry , Deoxy Sugars/chemistry , Glycosylation , Oligosaccharides/chemistry
4.
J Org Chem ; 82(7): 3926-3934, 2017 04 07.
Article in English | MEDLINE | ID: mdl-28281755

ABSTRACT

The use of a combination of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and ß-pinene permits the removal of 2-naphthylmethyl (Nap) ether protecting groups on highly sensitive substrates. The reaction tolerates both acid and base sensitive protecting groups, and products are afforded in 68-96% yield. The utility of the method is demonstrated by the removal of the Nap protecting groups on highly sensitive 2,6-dideoxy-sugar disaccharides.


Subject(s)
Benzoquinones/chemistry , Bridged Bicyclo Compounds/chemistry , Ethers/chemistry , Monoterpenes/chemistry , Bicyclic Monoterpenes , Spectrum Analysis/methods
5.
Bioorg Med Chem ; 23(3): 632-47, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25549898

ABSTRACT

The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, ß-lactamase resistant monocyclic ß-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine ß-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) ß-lactamase producing Moraxella catarrhalis clinical isolates.


Subject(s)
Anti-Bacterial Agents/pharmacology , Moraxella catarrhalis/drug effects , Mycobacterium tuberculosis/drug effects , beta-Lactams/pharmacology , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests , Moraxella catarrhalis/enzymology , Mycobacterium tuberculosis/enzymology , beta-Lactams/chemistry , beta-Lactams/metabolism
6.
J Org Chem ; 79(20): 9826-9, 2014 Oct 17.
Article in English | MEDLINE | ID: mdl-25211277

ABSTRACT

A concise gram-scale synthesis of protected colitose thioglycosides for use in bacterial carbohydrate antigen synthesis is described. The synthesis proceeds in six steps and 59-70% overall yield from commercially available l-fucose, making it the most efficient route reported to date. Key steps include regioselective installation of a thiocarbonate using catalytic dioctyltin dichloride (10 mol%) and a tris(trimethylsilyl)silane-mediated radical deoxygenation.


Subject(s)
Deoxy Sugars/chemical synthesis , Fucose/chemistry , Thioglycosides/chemical synthesis , Deoxy Sugars/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Silanes/chemistry , Thioglycosides/chemistry
7.
Org Lett ; 15(16): 4170-3, 2013 Aug 16.
Article in English | MEDLINE | ID: mdl-23906042

ABSTRACT

N-Sulfonyl imidazoles activate 2-deoxy-sugar hemiacetals for glycosylation presumably by converting them into glycosyl sulfonates in situ. By matching the leaving group ability of the sulfonate with the reactivity of the donor, it is possible to obtain ß-specific glycosylation reactions. The reaction serves as proof of the principle that, by choosing promoters that can modulate the reactivity of active intermediates, it is possible to place glycosylation reactions entirely under reagent control.

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