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Attacking Mycobacterium tuberculosis with designer drugs Chem 3000; Literature review Shayne Rybchinski March 26, 2009 Taken from: Davis, N., Decoding

Dec 19, 2015

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  • Slide 1
  • Attacking Mycobacterium tuberculosis with designer drugs Chem 3000; Literature review Shayne Rybchinski March 26, 2009 Taken from: Davis, N., Decoding Genomes Of Tuberculosis Bacteria, accessed online at http://medicineworld.org/images/news-blogs/ on March 12, 2009http://medicineworld.org/images/news-blogs/ Taken from: Casanas, B.,Tuberculosis -- Are You at Risk?, Accessed online at http://a.abcnews.com/Health/Germs on March 12, 2009
  • Slide 2
  • * * Taken from: Fordyce, M., What is XDR-TB? Found online at www.clinicalcorrelations.org/?m=200702 on March 12, 2009 www.clinicalcorrelations.org/?m=200702 The Resurgence of an insidious disease: 1 st line drugs: Isoniazid Rifampicin Streptomycin Ethambutol 2 nd line drugs: Amikacin Kanamycin Capreomycin Fluoroquinilone
  • Slide 3
  • Prado, P., Ledeit, H., Michel, S., Kock, M., Darbord, J. C., Cole, S. T., Tillequin, F., and Brodin, P. Bioorganic and Medicinal Chemistry 14 (2006) 5423-5428 Synethesis and antimycobacterial evaluation of benzopyran analgoes. Bioorganic and Medicinal Chemistry 15 (2007) 2177-2186 Prado, P., Janin Y. L., Saint-Joanis, B., Brodin, P., Michel, S., Koch, M., Cole, S. T., Tiellequin, F., and Bost, P. Alvey L., Prado, S., Huteau, V., Saint-Joanis, B., Michel, S., Koch, M., Cole, S. T., Tillequin, F., and Janin, Y. L., A new synthetic access to furo[3.2,-f]- chromene analogues of anantimycobacterial Bioorganic and Medicinal Chemistry 16 (2008) 8264-8272 Benzofuro[3,2- f][1]benzopyrans: A new class of antitubercular agents
  • Slide 4
  • Drug Design Strategy: Inspiration from Nature Chemical Design and Synthesis of Structural Analogues with Potential Acitivity Assay anti- mycobacterium activity Test selectivity by testing toxic activity against other bacteria Assay cyto-toxicity in mammalian cells In vivo assays Determination of specific activity Usnic Acid 3,3-dimethyl-3Hbenzofuro[3,2-][1]benzopyran DBB
  • Slide 5
  • Fused dimethylpyran rings in nature: Benzopyran methylripariochromene A Pyranoflavanone 5-methyllupinifoliol Acridone alkaloid acrynycine
  • Slide 6
  • Design Targets: OH, OCO X = H, OCOCH 3 X = COH, CO, X = CH, N R = H, Me
  • Slide 7
  • 3,3-dimethyl-3Hbenzofuro[3,2- f][1]benzopyran as a synthetic target: OH 12 hrs 1.3-dichloro benzene 3,3-dimethyl- 3Hbenzofuro-[3,2]- [1]benzopyran Dimethyl- propargyl ether 3-chloro-3methyl-1-butyne + 2-hydroxydibenzofuran Prado, P., Ledeit, H., Michel, S., Kock, M., Darbord, J. C., Cole, S. T., Tillequin, F., and Brodin, P., Bioorganic and Medicinal Chemistry 14 (2006) 5423-5428
  • Slide 8
  • Pd-C H 2 Ethanol Addition across the C-C -bond : OsO 4 NMNO 1. Acetic Anhydride 2. H 2 O NNCdM 2-butanone Prado, P., Ledeit, H., Michel, S., Kock, M., Darbord, J. C., Cole, S. T., Tillequin, F., and Brodin, P., Bioorganic and Medicinal Chemistry 14 (2006) 5423-5428
  • Slide 9
  • Biological Activity; MIC 99 ( g/ml): Isoniazid (INH) M. smegmatis5 13013 M. Tuberculosis H37Ra 55600.1 M. Tuberculosis INH resistant 51---5 E. coli >600>5005--- S. aureus >100ND--- N. asteroides 15 --- Vero cells 80100--- Macrophages 80>100---
  • Slide 10
  • Drug Design Strategy: Inspiration from Nature Chemical Design and Synthesis of Structural Analogues with Potential Acitivity Assay anti- mycobacterium activity Test selectivity by testing toxic activity against other bacteria Assay cyto-toxicity in mammalian cells In vivo assays Determination of specific activity
  • Slide 11
  • Replacement of the furan ring of dibenzofuran: Ethanol NaBH 3 CH 2 Cl 2, k10 1.2-dichloro- benzene, DBU CuCl 2 2H 2 O, inert atm. 1. CH 2 Cl 2 2. AlCl 3 Prado, P., Janin Y. L., Saint-Joanis, B., Brodin, P., Michel, S., Koch, M., Cole, S. T., Tiellequin, F., and Bost, P., Bioorganic and Medicinal Chemistry 15 (2007) 2177-2186
  • Slide 12
  • M. smegmatis20 504 M. Tuberculosis H37Ra 20403062 Vero cells163275ND Biological Activity; MIC 95 ( g/ml):
  • Slide 13
  • Synthesis of 4-pyridal derivatives: Alvey L., Prado, S., Huteau, V., Saint-Joanis, B., Michel, S., Kock, M., Cole, S. T., Tillequin, F., and Janin, Y. L., Bioorganic and Medicinal Chemistry 16 (2008) 8264-8272
  • Slide 14
  • , 12 hrs Inert atm. 1.3-dichloro benzene 2. DBU, CuCl 2 2H 2 0 3. C 4 H 5 Cl EtOH H 2 O Na 2 S 2 O 5 Synthesis of 4-pyridal analogues:
  • Slide 15
  • M. smegmatis >50036.2 M. Tuberculosis H37Ra 322.53 Biological Activity; MIC 95 ( g/ml):
  • Slide 16
  • Summary and Conclusions: Pyridine containing DBB analogues have excellent potential to develop new TB drugs and shorten time necessary for effective treatment. Minor perturbations in structure can have a large impact on biological activity The design of new drugs against TB remains a global imperative
  • Slide 17
  • Claissen Rearrangement:
  • Slide 18
  • Acronycines: