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
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
Benzofuro[3,2Synethesis and
f][1]benzopyrans: A new antimycobacterial evaluation
class of antitubercular
of benzopyran analgoes.
agents
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.
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.
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.,
Drug Design Strategy:
O
OH
O
O
Inspiration from NatureOH
HO
O
O
O
Usnic Acid
In vivo assays
Chemical Design and
Synthesis of Structural
O with Potential
Analogues
3,3-dimethyl-3Hbenzofuro[3,2-ƒ][1]benzopyran
Acitivity
DBB
Assay antimycobacterium
activity
Assay cyto-toxicity in
mammalian cells
Determination of specific activity
Test selectivity by testing
toxic activity against
other bacteria
Fused dimethylpyran rings in nature:
OMe
O
OH
O
O
O
OH
O
H3COC
O
Benzopyran methylripariochromene A
Pyranoflavanone 5-methyllupinifoliol
O
O
N
O
O
O
Acridone alkaloid acrynycine
Design Targets:
O
O
X
X
R
O
O
X
O
O
OH, OCO
X = H,
OCOCH3
O
X
X = COH, CO,
X = CH, N
R = H, Me
3,3-dimethyl-3Hbenzofuro[3,2f][1]benzopyran as a synthetic target:
Δ
12 hrs
O
O
OH
OH
Cl
O
1.3-dichloro
benzene
3,3-dimethyl3Hbenzofuro-[3,2ƒ][1]benzopyran
O
Dimethylpropargyl ether
+
O
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
Addition across the C-C π-bond:
O
Pd-C
H2
Ethanol
O
O
OCOCH3
O
H3COCO
OsO4
NMNO
1. Acetic
Anhydride
O
O
OH
HO
O
2. H2O
O
NNCdM
Δ
2-butanone
O
O
O
O
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
Biological Activity; MIC99(μg/ml):
OH
HO
O
O
O
O
O
Isoniazid
(INH)
O
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
---
---
Drug Design Strategy:
Inspiration from Nature
In vivo assays
Chemical Design and
Synthesis of Structural
Analogues with Potential
Acitivity
Assay antimycobacterium
activity
Assay cyto-toxicity in
mammalian cells
Determination of specific activity
Test selectivity by testing
toxic activity against
other bacteria
Replacement of the furan ring of
dibenzofuran:
O
1.2-dichlorobenzene, Δ
O
O
DBU
CuCl2∙2H2O,
inert atm.
N
+
O
O
CH2Cl2,
k10
O
OH
OH
Br
+
O
O
Ethanol
NaBH3
O
O
O
OH
O
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
O
H
O
1. CH2Cl2
2. AlCl3
O
Cl
O
+
OH
Biological Activity; MIC95 (μg/ml):
O
O
OH
M.
smegmatis
O
O
O
O
O
H
O
20
20
50
4
M.
Tuberculosis
H37Ra
20
40
30
62
Vero cells
16
32
75
ND
Synthesis of 4-pyridal derivatives:
O
O
O
N
O
O
N
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
Synthesis of 4-pyridal analogues:
1.3-dichloro
benzene
R
R
O
O
Δ, 12 hrs
Inert atm.
X
O
X
O
N , inert atm
1.
2. DBU, CuCl2∙2H20
3. C4H5Cl
O
R
EtOH
H2O
Na2S2O5
+
X
N
O
O
R
OH
X
O
Biological Activity; MIC95 (μg/ml):
O
O
N
O
N
O
O
O
>500
3
6.2
32
2.5
3
M. smegmatis
M.
Tuberculosis
H37Ra
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
O
OH
H
O
Acronycines: