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 at http://a.abcnews.com/Health/Germs on March 12,
Attacking Mycobacterium tuberculosis with designer drugs Chem 3000; Literature review Shayne Rybchinski March 26, 2009 Taken from: Davis, N., Decoding.
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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 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 • Ethambutol
2nd 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:
O
OH
OH OO
OH
OO
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
O
O
Determination of specific activity
Usnic Acid
3,3-dimethyl-3Hbenzofuro[3,2-ƒ][1]benzopyranDBB
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
O
OHΔ
12 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-CH2
Ethanol
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 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:
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
X
N
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:
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