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Attacking Mycobacterium tuberculosis with designer drugs

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, 2009.

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Attacking Mycobacterium tuberculosis with designer drugs

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  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, 2009 Taken from: Casanas, B.,Tuberculosis -- Are You at Risk?, Accessed online athttp://a.abcnews.com/Health/Germs on March 12, 2009

  2. The Resurgence of an insidious disease: 1st line drugs: • Isoniazid • Rifampicin • Streptomycin • Ethambutol * 2nd line drugs: • Amikacin • Kanamycin • Capreomycin • Fluoroquinilone * Taken from: Fordyce, M., What is XDR-TB? Found online at www.clinicalcorrelations.org/?m=200702 on March 12, 2009

  3. Benzofuro[3,2-f][1]benzopyrans: A new class of antitubercular agents Synethesis and antimycobacterial evaluation of benzopyrananalgoes. Bioorganic and Medicinal Chemistry 15 (2007) 2177-2186 Bioorganic and Medicinal Chemistry 14 (2006) 5423-5428 Prado, P., Ledeit, H., Michel, S., Kock, M., Darbord, J. C., Cole, S. T., Tillequin, F., and Brodin, P. Prado, P., Janin Y. L., Saint-Joanis, B., Brodin, P., Michel, S., Koch, M., Cole, S. T., Tiellequin, F., and Bost, P. A new synthetic access to furo[3.2,-f]- chromene analogues of anantimycobacterial Bioorganic and Medicinal Chemistry 16 (2008) 8264-8272 Alvey L., Prado, S., Huteau, V., Saint-Joanis, B., Michel, S., Koch, M., Cole, S. T., Tillequin, F., and Janin, Y. L.,

  4. Drug Design Strategy: Chemical Design and Synthesis of Structural Analogues with Potential Acitivity Inspiration from Nature 3,3-dimethyl-3Hbenzofuro[3,2-ƒ][1]benzopyran DBB Usnic Acid Assay anti-mycobacterium activity In vivo assays Assay cyto-toxicity in mammalian cells Test selectivity by testing toxic activity against other bacteria Determination of specific activity

  5. Fused dimethylpyran rings in nature: Pyranoflavanone 5-methyllupinifoliol Benzopyranmethylripariochromene A Acridone alkaloid acrynycine

  6. Design Targets: OH, OCO X = H, OCOCH3 X = CH, N R = H, Me X = COH, CO,

  7. 3,3-dimethyl-3Hbenzofuro[3,2-f][1]benzopyran as a synthetic target: Δ 12 hrs OH 1.3-dichloro benzene Dimethyl- propargyl ether 3-chloro-3methyl-1-butyne + 3,3-dimethyl- 3Hbenzofuro-[3,2ƒ]- [1]benzopyran 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

  8. Addition across the C-C π-bond: Pd-C H2 Ethanol OsO4 NMNO 1. Acetic Anhydride 2. H2O NNCdM Δ 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

  9. Biological Activity; MIC99(μg/ml):

  10. Drug Design Strategy: Chemical Design and Synthesis of Structural Analogues with Potential Acitivity Inspiration from Nature Assay anti-mycobacterium activity In vivo assays Assay cyto-toxicity in mammalian cells Test selectivity by testing toxic activity against other bacteria Determination of specific activity

  11. Replacement of the furan ring of dibenzofuran: DBU CuCl2∙2H2O, inert atm. 1.2-dichloro- benzene, Δ CH2Cl2, k10 Ethanol NaBH3 1. CH2Cl2 2. AlCl3 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

  12. Biological Activity; MIC95 (μg/ml):

  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

  14. Synthesis of 4-pyridal analogues: 1.3-dichloro benzene Δ, 12 hrs Inert atm. 2. DBU, CuCl2∙2H20 3. C4H5Cl EtOH H2O Na2S2O5

  15. Biological Activity; MIC95 (μg/ml):

  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

  17. Claissen Rearrangement:

  18. Acronycines:

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