A strategy for improvement of physicochemical proper es of an ...
Graduate Category: Physical and Life Sciences Degree Level: PhD Abstract ID# 193
A strategy for improvement of physicochemical proper4es of an4-‐malarial agents.
BIOLOGICAL ASSAY RESULTS
Naimee Mehta,1 William Devine,1 Richard ScioG,2 and Michael Pollastri. 1
R1
1Northeastern Department of Chemistry & Chemical Biology, 360 HunPngton Avenue, Boston, MA 02115. 2Walter Reed Army
Molecule D6 IC50 Name (μM)
InsPtute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910. ysiand Life Sciences
ABSTRACT
OUTPUT OF LIBRARY SHAPING
Malaria is an infecPous disease caused by several protozoan parasiPc species, including Plasmodium falciparum, and is transmiTed by the bites of female anopheles mosquitoes. Malaria poses a significant health threat with over 250 million cases worldwide, with a majority of the affected populaPon living within underdeveloped countries. A study in 2010 reports that 80% of esPmated malaria deaths occur in just 14 countries majority being in Africa. Novel, economic and effecPve drugs are required to curb the emerging resistance that renders the current drug arsenal ineffecPve. We recently discovered a highly potent anP-‐malarial compound NEU-‐961 starPng from NEU-‐617, which was derived from the approved human anP-‐cancer therapeuPc lapaPnib, which is also a potent growth inhibitor of Trypanosoma brucei (which causes African sleeping sickness)1. The lead compound, although highly acPve, has poor physicochemical properPes. In order to improve this a virtual library of analogs of the lead was designed based on 3D shape and electrostaPcs similarity. PrioriPzed compounds from this library were synthesized and tested in parasite growth assays and in physicochemical properPes assays. Results from this campaign will be presented.
T brucei Host cell Tox EC50 TC50 (μM) (μM)
LogP
LLE*
NEU-‐961
0.01
0.08
14.35
6.4
1.72
NEU-‐1018
0.03
> 50.0
> 100.00
3.5
4.04
NEU-‐1019
0.13
5.43
> 100.00
2.9
3.98
NEU-‐1020
2.11
> 50.0
> 100.00
1.9
3.76
NEU-‐1021
0.06
2.51
50.47
2.7
4.54
NEU-‐1022
0.15
0.62
15.52
2.7
4.12
NEU-‐1023
0.10
0.60
> 100.00
3.4
3.59
NEU-‐1024
0.13
2.97
> 100.00
2.5
4.35
NEU-‐1025
0.06
1.46
10.72
3.5
3.72
NEU-‐1026
0.25
0.27
5.64
4.1
2.51
NEU-‐1027
0.22
0.91
17.23
2.3
4.37
NEU-‐1028
0.16
> 50.0
> 100.00
2.2
4.63
NEU-‐1029
0.01
0.22
16.14
4.6
3.33
NEU-‐1030
0.23
> 50.0
> 100.00
4.7
1.91
NEU-‐1031
0.07
0.65
> 100.00
5.2
1.92
NEU-‐1022 (magenta), NEU-‐1028-‐(purple) and NEU-‐1021 (grey) overlaid upon NEU-‐961 (gold)
ANALOG SYNTHESIS
BACKGROUND
O
O S O
NH
Cl
HN O
O
F
HN
Cl
N N
Lapa4nib Pfal D6 -‐ 0.466 μM Tbb -‐ 1.4747 μM TC50 -‐ 74.13 μM LogP -‐ 4.64 MWt -‐ 581.0
HN
N
O Cl
N
N O
F
O S N O
F TruncaPons
N NEU-‐961 Pfal D6 -‐ 0.007 Tbb -‐ 0.079 TC50 -‐ 14.35 LogP -‐ 6.43 MWt -‐ 617.1
Molecule D6 IC50 Name (μM)
T brucei EC50 (μM)
NEU-‐735
0.79
0.23
NEU-‐736
> 15.0
0.18
NEU-‐964
0.92
0.528
N NEU-‐617 Pfal D6 -‐ 0.228 Tbb -‐ 0.042 TC50 -‐ >50.0 LogP -‐ 7.31 MWt -‐ 541.0
RATIONALE AND STRATEGY Compound design ra4onale • Size and lipophilicity are current limitaPons ofNEU961 • TruncaPon of head group led to flat SAR – this is therefore a good region to focus on reducPon of LogP. Strategy • Enumerated a virtual library (VL) using heterocyclic amines • VL was filtered for properPes (MW < 500, LogP
A strategy for improvement of physicochemical proper4es of an4-‐malarial agents.
BIOLOGICAL ASSAY RESULTS
Naimee Mehta,1 William Devine,1 Richard ScioG,2 and Michael Pollastri. 1
R1
1Northeastern Department of Chemistry & Chemical Biology, 360 HunPngton Avenue, Boston, MA 02115. 2Walter Reed Army
Molecule D6 IC50 Name (μM)
InsPtute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910. ysiand Life Sciences
ABSTRACT
OUTPUT OF LIBRARY SHAPING
Malaria is an infecPous disease caused by several protozoan parasiPc species, including Plasmodium falciparum, and is transmiTed by the bites of female anopheles mosquitoes. Malaria poses a significant health threat with over 250 million cases worldwide, with a majority of the affected populaPon living within underdeveloped countries. A study in 2010 reports that 80% of esPmated malaria deaths occur in just 14 countries majority being in Africa. Novel, economic and effecPve drugs are required to curb the emerging resistance that renders the current drug arsenal ineffecPve. We recently discovered a highly potent anP-‐malarial compound NEU-‐961 starPng from NEU-‐617, which was derived from the approved human anP-‐cancer therapeuPc lapaPnib, which is also a potent growth inhibitor of Trypanosoma brucei (which causes African sleeping sickness)1. The lead compound, although highly acPve, has poor physicochemical properPes. In order to improve this a virtual library of analogs of the lead was designed based on 3D shape and electrostaPcs similarity. PrioriPzed compounds from this library were synthesized and tested in parasite growth assays and in physicochemical properPes assays. Results from this campaign will be presented.
T brucei Host cell Tox EC50 TC50 (μM) (μM)
LogP
LLE*
NEU-‐961
0.01
0.08
14.35
6.4
1.72
NEU-‐1018
0.03
> 50.0
> 100.00
3.5
4.04
NEU-‐1019
0.13
5.43
> 100.00
2.9
3.98
NEU-‐1020
2.11
> 50.0
> 100.00
1.9
3.76
NEU-‐1021
0.06
2.51
50.47
2.7
4.54
NEU-‐1022
0.15
0.62
15.52
2.7
4.12
NEU-‐1023
0.10
0.60
> 100.00
3.4
3.59
NEU-‐1024
0.13
2.97
> 100.00
2.5
4.35
NEU-‐1025
0.06
1.46
10.72
3.5
3.72
NEU-‐1026
0.25
0.27
5.64
4.1
2.51
NEU-‐1027
0.22
0.91
17.23
2.3
4.37
NEU-‐1028
0.16
> 50.0
> 100.00
2.2
4.63
NEU-‐1029
0.01
0.22
16.14
4.6
3.33
NEU-‐1030
0.23
> 50.0
> 100.00
4.7
1.91
NEU-‐1031
0.07
0.65
> 100.00
5.2
1.92
NEU-‐1022 (magenta), NEU-‐1028-‐(purple) and NEU-‐1021 (grey) overlaid upon NEU-‐961 (gold)
ANALOG SYNTHESIS
BACKGROUND
O
O S O
NH
Cl
HN O
O
F
HN
Cl
N N
Lapa4nib Pfal D6 -‐ 0.466 μM Tbb -‐ 1.4747 μM TC50 -‐ 74.13 μM LogP -‐ 4.64 MWt -‐ 581.0
HN
N
O Cl
N
N O
F
O S N O
F TruncaPons
N NEU-‐961 Pfal D6 -‐ 0.007 Tbb -‐ 0.079 TC50 -‐ 14.35 LogP -‐ 6.43 MWt -‐ 617.1
Molecule D6 IC50 Name (μM)
T brucei EC50 (μM)
NEU-‐735
0.79
0.23
NEU-‐736
> 15.0
0.18
NEU-‐964
0.92
0.528
N NEU-‐617 Pfal D6 -‐ 0.228 Tbb -‐ 0.042 TC50 -‐ >50.0 LogP -‐ 7.31 MWt -‐ 541.0
RATIONALE AND STRATEGY Compound design ra4onale • Size and lipophilicity are current limitaPons ofNEU961 • TruncaPon of head group led to flat SAR – this is therefore a good region to focus on reducPon of LogP. Strategy • Enumerated a virtual library (VL) using heterocyclic amines • VL was filtered for properPes (MW < 500, LogP
