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 on March 12, 2009http://medicineworld.org/images/news-blogs/ Taken from: Casanas, B.,Tuberculosis -- Are You at Risk?, Accessed online at on March 12, 2009

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

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) Synethesis and antimycobacterial evaluation of benzopyran analgoes. Bioorganic and Medicinal Chemistry 15 (2007) 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) Benzofuro[3,2- f][1]benzopyrans: A new class of antitubercular agents

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-ƒ][1]benzopyran DBB

Fused dimethylpyran rings in nature: Benzopyran methylripariochromene A Pyranoflavanone 5-methyllupinifoliol Acridone alkaloid acrynycine

Design Targets: OH, OCO X = H, OCOCH 3 X = COH, CO, X = CH, N R = H, Me

3,3-dimethyl-3Hbenzofuro[3,2- f][1]benzopyran as a synthetic target: OH Δ 12 hrs 1.3-dichloro benzene 3,3-dimethyl- 3Hbenzofuro-[3,2ƒ]- [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)

Pd-C H 2 Ethanol Addition across the C-C π-bond : OsO 4 NMNO 1. Acetic Anhydride 2. H 2 O 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)

Biological Activity; MIC 99 ( μg/ml): Isoniazid (INH) M. smegmatis M. Tuberculosis H37Ra M. Tuberculosis INH resistant E. coli >600> S. aureus >100ND--- N. asteroides Vero cells Macrophages 80>100---

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

Replacement of the furan ring of dibenzofuran: Ethanol NaBH 3 CH 2 Cl 2, k dichloro- benzene, Δ 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)

M. smegmatis M. Tuberculosis H37Ra Vero cells163275ND Biological Activity; MIC 95 ( μ g/ml):

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)

Δ, 12 hrs Inert atm. 1.3-dichloro benzene 2. DBU, CuCl 2 ∙2H C 4 H 5 Cl EtOH H 2 O Na 2 S 2 O 5 Synthesis of 4-pyridal analogues:

M. smegmatis > M. Tuberculosis H37Ra Biological Activity; MIC 95 ( μ g/ml):

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

Claissen Rearrangement:

Acronycines: