1. Open Synthesis Network Project 1
Lead series for Visceral Leishmaniasis

2. Project Background
Lead series originating from screening of Pfizer internal collection
SCYX identified as initial hit:
To date, > 1,000 analogues have been made around this series
Some of the key exploration has been published
(Mowbray et.al. J.Med.Chem 2015 link)
Lead candidates have been identified and are undergoing advanced profiling
SCYX
L.donovani IC50: 5.8 µM
Open Source Chemistry

3. Open Source Chemistry Opportunity
DNDi have a clear need for back-up molecules within the series
DNDi have identified certain chemical avenues that require further exploration
These avenues have been broken down into various “work packages” exploring different areas of the scaffold
Open Source Chemistry

4. Open Source Chemistry Opportunity
Each Work Package provides concise data set around related molecules (20-30 compounds)
Each Work Package provides a list of target molecules that DNDI would like to have synthesized and tested for potency
Within each Work Package there is the scope for participants to propose and synthesize their own analogues, alongside the analogues suggested by DNDi
New proposed molecules will need to by cleared and confirmed by DNDi beforehand in order to avoid duplication
Open Source Chemistry

5. Work packages for chemistry investigation
Open alkyl chain ureas A
Functionality scan of pyridine D
ß-Proline analogues E
Cyclized core
Piperazine ureas
Fluorinated pyrazole analogues & other targets C B F
Open Source Chemistry

6. Work packages for chemistry investigation
Open alkyl chain ureas A
Functionality scan of pyridine D
ß-Proline analogues E
Cyclized core
Piperazine ureas
Fluorinated pyrazole analogues & other targets C B F
Open Source Chemistry

7. Work package A Open Source Chemistry
Open alkyl chain ureas
Work package A
Handful of acyclic alkyl ureas have been made; activity observed but deprioritized
DNDi will provide data set of compounds made within this sub-series (approx. 30)
Stability in rodent microsomes seems to be an issue / area for improvement.
Balance of ClogP is key for keeping potency and achieving metabolic stability
Focus of work package: Improve potency and improve rodent microsomal stability via exploration / combination approach:
Examples of target compounds:
Library scans
(suitable for parallel synthesis from common intermediate)
For list of DNDi targets, see associated sdf file
Open Source Chemistry

8. Work package A Open Source Chemistry
Open alkyl chain ureas
Work package A
Handful of acyclic alkyl ureas have been made; activity observed but deprioritized
DNDi will provide data set of compounds made within this sub-series (approx. 30)
Stability in rodent microsomes seems to be an issue / area for improvement.
Balance of ClogP is key for keeping potency and achieving metabolic stability
Focus of work package: Improve potency and improve rodent microsomal stability via exploration / combination approach:
Examples of target compounds:
Alkylation and other derivatization around urea
(May require some bespoke synthetic investigation)
For list of DNDi targets, see associated sdf file
Open Source Chemistry

9. Work packages for chemistry investigation
Open alkyl chain ureas A
Functionality scan of pyridine D
ß-Proline analogues E
Cyclized core
Piperazine ureas
Fluorinated pyrazole analogues & other targets C B F
Open Source Chemistry

10. Work package B Open Source Chemistry
Piperazine ureas
Work package B
Examples of piperazine and homopiperazine ureas have been made (approx. 35 analogues), with activity observed.
Data set of existing piperazines and other compounds will be provided
Metabolic stability and optimization of potency needs to be addresses
DNDI
L.Infantum IC50: 0.45 µM
HLM 51 µL/min/mg.pr
DNDI
L.Infantum IC50: µM
HLM 51 µL/min/mg.pr
Examples of target compounds:
Further exploration of this sub-series:
(Library analoging, approximately compounds, relatively straightforward synthesis)
For list of DNDi targets, see associated sdf file
Open Source Chemistry

11. Work package B Open Source Chemistry
Piperazine ureas
Work package B
Examples of piperazine and homopiperazine ureas have been made (approx. 35 analogues), with activity observed.
Data set of existing piperazines and other compounds will be provided
Metabolic stability and optimization of potency needs to be addresses
DNDI
L.Infantum IC50: 0.45 µM
HLM 51 µL/min/mg.pr
DNDI
L.Infantum IC50: µM
HLM 51 µL/min/mg.pr
Examples of target compounds:
Combine with substituted pyrazole & triazole (Straightforward synthesis)
For list of DNDi targets, see associated sdf file
Open Source Chemistry

12. Work packages for chemistry investigation
Open alkyl chain ureas A
Functionality scan of pyridine D
ß-Proline analogues E
Cyclized core
Piperazine ureas
Fluorinated pyrazole analogues & other targets C B F
Open Source Chemistry

13. Work package C Open Source Chemistry
Cyclized core
Work package C
Cyclization of the core to give a partially saturated [5.6] system has demonstrated some potential but is relatively unexplored
Relevant data set will be provided (4 compounds)
Exploration of this chemical sub-series may require development of target-specific chemistry
Examples of target compounds:
For list of DNDi targets, see associated sdf file
Open Source Chemistry

14. Work packages for chemistry investigation
Open alkyl chain ureas A
Functionality scan of pyridine D
ß-Proline analogues E
Cyclized core
Piperazine ureas
Fluorinated pyrazole analogues & other targets C B F
Open Source Chemistry

15. Functionality scan of pyridine
Work package D
Replacement of 2-pyridyl on left-hand side (LHS) has been investigated, but not necessarily for more advanced right hand sides (RHS)
Relevant data set will be provided (approx. 20 compounds)
New chemistry could be developed to allow parallel synthesis; otherwise this requires bespoke synthesis for each analogue (approx. 4 steps)
Examples of target compounds:
For list of DNDi targets, see associated sdf file
Open Source Chemistry

16. Work packages for chemistry investigation
Open alkyl chain ureas A
Functionality scan of pyridine D
ß-Proline analogues E
Cyclized core
Piperazine ureas
Fluorinated pyrazole analogues & other targets C B F
Open Source Chemistry

17. Work package E Open Source Chemistry
ß-Proline analogues
Work package E
ß-Proline analogues showed some promise but have been deprioritized in favour of pyrrolidine ureas, mainly due to issues of metabolic stability
Data set of compounds can be provided
Ideally suited to synthesis of single building block followed by analoguing through parallel synthesis
DNDI
L.Infantum IC50: 0.60 µM
MRC5 CC50 >64 µM
PMM CC50 >64 µM
Examples of target compounds:
Further investigation + other ring variations?
For list of DNDi targets, see associated sdf file
Open Source Chemistry

18. Work packages for chemistry investigation
Open alkyl chain ureas A
Functionality scan of pyridine D
ß-Proline analogues E
Cyclized core
Piperazine ureas
Fluorinated pyrazole analogues & other targets C B F
Open Source Chemistry

19. Fluorinated pyrazole analogues & other targets
Work package F
Substitution of the 4-position of the pyrazole has been shown to be advantageous, however certain analogues have yet to be synthesized:
Expected to be Synthetically challenging
Examples of target compounds:
For list of DNDi targets, see associated sdf file
Open Source Chemistry