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Development of benzo[1,4]oxazines as biofilm inhibitors and dispersal agents against Vibrio cholerae.

Warner CJ, Cheng AT, Yildiz FH, Linington RG - Chem. Commun. (Camb.) (2015)

Bottom Line: Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections.However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence.Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, California, 95064, USA. rliningt@ucsc.edu.

ABSTRACT
Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections. However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence. Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

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The total synthesis of the benzo[1,4]oxazine biofilm inhibitor 1. Reagents and conditions: (i) HNO3, Ac2O, 0 °C to rt, 1 hour, 94% yield; (ii) 4 eq. AlCl3, DCM, 0 °C to reflux, 3 hours, 89% yield; (iii) 4 eq. BnBr, 4 eq. K2CO3, 1 : 1 DCM/MeOH, reflux, 3 hours, 97% yield; (iv) 4 eq. SnCl2, 3 : 1 EtOH/6N HCl, rt to reflux, 45 minutes, 81% yield; (v) 1.1 eq. pyruvoyl chloride, 1.5 eq. pyridine, DCM, 0 °C to rt, 90 minutes, 65% yield; (vi) 2% Pd(OH)2/C, 4 eq. 1,4-cyclohexadiene, EtOH, 50 °C, 2 minutes, 81% yield; (vii) 1.2 eq. MsCl, 1.5 eq. NEt3, DCM, 0 °C to rt, 90 minutes, 82% yield.
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sch1: The total synthesis of the benzo[1,4]oxazine biofilm inhibitor 1. Reagents and conditions: (i) HNO3, Ac2O, 0 °C to rt, 1 hour, 94% yield; (ii) 4 eq. AlCl3, DCM, 0 °C to reflux, 3 hours, 89% yield; (iii) 4 eq. BnBr, 4 eq. K2CO3, 1 : 1 DCM/MeOH, reflux, 3 hours, 97% yield; (iv) 4 eq. SnCl2, 3 : 1 EtOH/6N HCl, rt to reflux, 45 minutes, 81% yield; (v) 1.1 eq. pyruvoyl chloride, 1.5 eq. pyridine, DCM, 0 °C to rt, 90 minutes, 65% yield; (vi) 2% Pd(OH)2/C, 4 eq. 1,4-cyclohexadiene, EtOH, 50 °C, 2 minutes, 81% yield; (vii) 1.2 eq. MsCl, 1.5 eq. NEt3, DCM, 0 °C to rt, 90 minutes, 82% yield.

Mentions: We recently reported the development of two high throughout image-based screens capable of identifying biofilm inhibitors against the Gram-negative pathogens V. cholerae and Pseudomonas aeruginosa.8–10 Screening of our natural product library, compromising of over 6000 prefractions, identified the aureomycin chromophore 1 as a moderate inhibitor of V. cholerae biofilms (biofilm inhibitory concentration (BIC50) = 63 μM). Given the structural novelty of this scaffold compared with other biofilm inhibitors, and the unusual biofilm inhibitory phenotype observed in the primary screening images, we elected to develop the benzo[1,4]oxazine scaffold through medicinal chemistry optimization in order to identify key elements of the required pharmacophore, and generate analogues with improved potency and pharmacological properties.11 Key to this approach was the formation of the α-keto-amide 7 and its subsequent application in a debenzylation–cyclization strategy to form hemi-acetal 8. Gratifyingly, treatment of the α-ketoamide 7 (formed in 5 steps from the commercially available ester 2) with 2% Pd(OH)2 on charcoal and four equivalents of 1,4-cyclohexadiene in ethanol at 50 °C enabled formation of the cyclic hemi-acetal 8 in excellent yield on a multi-gram scale with reaction times of less than 5 minutes. Dehydration of the acetal afforded the target molecule in 7 steps on a multigram scale (Scheme 1).


Development of benzo[1,4]oxazines as biofilm inhibitors and dispersal agents against Vibrio cholerae.

Warner CJ, Cheng AT, Yildiz FH, Linington RG - Chem. Commun. (Camb.) (2015)

The total synthesis of the benzo[1,4]oxazine biofilm inhibitor 1. Reagents and conditions: (i) HNO3, Ac2O, 0 °C to rt, 1 hour, 94% yield; (ii) 4 eq. AlCl3, DCM, 0 °C to reflux, 3 hours, 89% yield; (iii) 4 eq. BnBr, 4 eq. K2CO3, 1 : 1 DCM/MeOH, reflux, 3 hours, 97% yield; (iv) 4 eq. SnCl2, 3 : 1 EtOH/6N HCl, rt to reflux, 45 minutes, 81% yield; (v) 1.1 eq. pyruvoyl chloride, 1.5 eq. pyridine, DCM, 0 °C to rt, 90 minutes, 65% yield; (vi) 2% Pd(OH)2/C, 4 eq. 1,4-cyclohexadiene, EtOH, 50 °C, 2 minutes, 81% yield; (vii) 1.2 eq. MsCl, 1.5 eq. NEt3, DCM, 0 °C to rt, 90 minutes, 82% yield.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288701&req=5

sch1: The total synthesis of the benzo[1,4]oxazine biofilm inhibitor 1. Reagents and conditions: (i) HNO3, Ac2O, 0 °C to rt, 1 hour, 94% yield; (ii) 4 eq. AlCl3, DCM, 0 °C to reflux, 3 hours, 89% yield; (iii) 4 eq. BnBr, 4 eq. K2CO3, 1 : 1 DCM/MeOH, reflux, 3 hours, 97% yield; (iv) 4 eq. SnCl2, 3 : 1 EtOH/6N HCl, rt to reflux, 45 minutes, 81% yield; (v) 1.1 eq. pyruvoyl chloride, 1.5 eq. pyridine, DCM, 0 °C to rt, 90 minutes, 65% yield; (vi) 2% Pd(OH)2/C, 4 eq. 1,4-cyclohexadiene, EtOH, 50 °C, 2 minutes, 81% yield; (vii) 1.2 eq. MsCl, 1.5 eq. NEt3, DCM, 0 °C to rt, 90 minutes, 82% yield.
Mentions: We recently reported the development of two high throughout image-based screens capable of identifying biofilm inhibitors against the Gram-negative pathogens V. cholerae and Pseudomonas aeruginosa.8–10 Screening of our natural product library, compromising of over 6000 prefractions, identified the aureomycin chromophore 1 as a moderate inhibitor of V. cholerae biofilms (biofilm inhibitory concentration (BIC50) = 63 μM). Given the structural novelty of this scaffold compared with other biofilm inhibitors, and the unusual biofilm inhibitory phenotype observed in the primary screening images, we elected to develop the benzo[1,4]oxazine scaffold through medicinal chemistry optimization in order to identify key elements of the required pharmacophore, and generate analogues with improved potency and pharmacological properties.11 Key to this approach was the formation of the α-keto-amide 7 and its subsequent application in a debenzylation–cyclization strategy to form hemi-acetal 8. Gratifyingly, treatment of the α-ketoamide 7 (formed in 5 steps from the commercially available ester 2) with 2% Pd(OH)2 on charcoal and four equivalents of 1,4-cyclohexadiene in ethanol at 50 °C enabled formation of the cyclic hemi-acetal 8 in excellent yield on a multi-gram scale with reaction times of less than 5 minutes. Dehydration of the acetal afforded the target molecule in 7 steps on a multigram scale (Scheme 1).

Bottom Line: Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections.However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence.Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, California, 95064, USA. rliningt@ucsc.edu.

ABSTRACT
Bacterial biofilms are estimated to be associated with over 65 percent of all nosocomial infections. However, no therapeutics have been approved by the FDA which directly mediate biofilm formation or persistence. Herein we report oxazine as a highly potent inhibitor, disperser and in the presence of the appropriate antibiotic eradicator of V. cholerae biofilms.

Show MeSH
Related in: MedlinePlus