Attacking Mycobacterium tuberculosis with designer

drugs Chem 3000; Literature reviewShayne 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 at http://a.abcnews.com/Health/Germs on March 12, 2009

*

* Taken from: Fordyce, M., What is XDR-TB? Found online at www.clinicalcorrelations.org/?m=200702 on March 12, 2009

The Resurgence of an insidious disease:

1st line drugs: • Isoniazid • Rifampicin • Streptomycin • Ethambutol2nd 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) 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

Drug Design Strategy:

OOH

OH OO

OH

OO

Inspiration from NatureChemical 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

O

O

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

ON

O O

O

O

OH

OO

OH

O

OMe

O

H3COC

O

O

O

O

Design Targets:

O

O

X

X

OH, OCOX = H, OCOCH3

O

X

X = COH, CO,

X = CH, NR = H, Me

XO

OR

3,3-dimethyl-3Hbenzofuro[3,2-f][1]benzopyran as a synthetic target:

O

O

O

OOH

Δ12 hrs

1.3-dichloro benzene 3,3-dimethyl-

3Hbenzofuro-[3,2ƒ]- [1]benzopyran

Cl

O

OH

+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

O

O

O

O

Pd-CH2Ethanol

Addition across the C-C π-bond:

O

O

OH

OH O

O

H3COCO

OCOCH3

O

O

O

O

O

OsO4 NMNO 1. Acetic

Anhydride

2. H2O

NNCdMΔ2-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

Biological Activity; MIC99(μg/ml):

Isoniazid (INH)

M. smegmatis

5 1 30 13

M. Tuberculosis H37Ra

5 5 60 0.1

M. Tuberculosis INH resistant

5 1 --- 5

E. coli >600 >500 5 ---S. aureus >100 ND --- ---N. asteroides

15 15 --- ---

Vero cells 80 100 --- ---Macrophages

80 >100 --- ---

O

O

O

O

O

O

OH

OH

Drug Design Strategy:

Inspiration from NatureChemical 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:

O

O

O

OH

O

O

OH

O

OEthanolNaBH3

O

O CH2Cl2,k10

1.2-dichloro-benzene, Δ

DBUCuCl2∙2H2O,inert atm.O

O O

OH

N

+

O

OH Br+

1. CH2Cl22. AlCl3 Cl

O

O

OH

+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

M. smegmatis

20 20 50 4

M. Tuberculosis H37Ra

20 40 30 62

Vero cells 16 32 75 ND

Biological Activity; MIC95 (μg/ml):O

OH O

O

OH

O

O

O

O

Synthesis of 4-pyridal derivatives:

O

ON

O

ON

O

O

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

Δ, 12 hrsInert atm.

1.3-dichloro benzene

XO

OR

O

OH

X

R

N , inert atm1.

2. DBU, CuCl2 2H∙ 203. C4H5ClO

O

XN

R

O

+ EtOHH2ONa2S2O5

Synthesis of 4-pyridal analogues:

OX

RO

M. smegmati

s>500 3 6.2

M. Tuberculosis H37Ra

32 2.5 3

O

O

O

O

NO

O

N

Biological Activity; MIC95 (μg/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:

O

H

O OH O

Acronycines: