Tag Archives: Malaria

Benzylic amine compounds

In order to support Github issue #504, I used my previously described Matched Molecular Pairs (MMP), coupled with ECFP regression, to create and prioritize benzylic amine substitutes. MMP approach has been described here

In this case, the lead compound had the smiles '

FC(F)OC1=CC=C(C=C1)C1=NN=C2C=NC=C(COC(=O)C3=CC=CC=C3)N12

'

When fed to the MMP program, this generated 285,618 compounds. I then filtered out all the compounds which had the amine at the desired spot, which then reduced the pool to 47 compounds. All of the compounds can be found here

These compounds then had their EC50 predicted after training a MLP on the 125 compounds taken from the Master List which were designated 'series 4' and had appropriate EC50 values. 

OSM PfATP4 competition hidden set prediction

The final hidden test set for the PfATP4 competition has been released here.

All of the 400 compounds contained in the "MASTER SHEET" section of the spreadsheet were submitted to predictions using our earlier described PfATP4 Ion Regulation Activity classification model.

  1. The “Predicted PfATP4 Ion Regulation Activity Class” is the predicted class for the actual molecule (being 1.0 = “active”, 0.0 = “inactive”, and 0.5 = “partially active”).

  2. The “PfATP4 Active Class Probability” is the probability of the actual molecule to be active.

Molecules are reported below in rank order with the most probable to be active at the top.

 

ID

Predicted PfATP4 Ion Regulation Activity Class

PfATP4 Active Class Probability

MMV006239

1.0

0.733

MMV021057

1.0

0.667

MMV676186

1.0

0.533

MMV688550

1.0

0.533

MMV461553

1.0

0.467

MMV676571

0.0

0.467

MMV019551

0.0

0.467

MMV688350

0.0

0.467

MMV001493

0.0

0.467

MMV688509

0.0

0.467

MMV688756

0.0

0.467

MMV676603

0.0

0.467

MMV689000

0.0

0.467

MMV024829

0.0

0.4

MMV688270

0.0

0.4

MMV161996

0.0

0.4

MMV020520

0.0

0.4

MMV021660

0.0

0.4

MMV011903

0.0

0.4

MMV688362

0.0

0.4

MMV687699

0.0

0.4

MMV688754

0.0

0.4

MMV688508

0.0

0.4

MMV047015

0.0

0.4

MMV676008

0.0

0.4

MMV688327

0.0

0.4

MMV688703

0.0

0.4

MMV676604

0.0

0.4

MMV688775

0.0

0.4

MMV689437

0.0

0.4

MMV637953

0.0

0.333

MMV688313

0.0

0.333

MMV407539

0.0

0.333

MMV676162

0.0

0.333

MMV688845

0.0

0.333

MMV675968

0.0

0.333

MMV687703

0.0

0.333

MMV687812

0.0

0.333

MMV687803

0.0

0.333

MMV675997

0.0

0.333

MMV663250

0.0

0.333

MMV1088520

0.0

0.333

MMV676478

0.0

0.333

MMV021375

0.0

0.333

MMV688921

0.0

0.333

MMV687813

0.0

0.333

MMV000011

0.0

0.333

MMV688994

0.0

0.333

MMV020591

0.0

0.267

MMV020710

0.0

0.267

MMV003152

0.0

0.267

MMV676269

0.0

0.267

MMV676270

0.0

0.267

MMV202553

0.0

0.267

MMV675998

0.0

0.267

MMV689709

0.0

0.267

MMV611037

0.0

0.267

MMV019189

0.0

0.267

MMV687180

0.0

0.267

MMV090930

0.0

0.267

MMV688371

0.0

0.267

MMV687749

0.0

0.267

MMV668727

0.0

0.267

MMV688271

0.0

0.267

MMV676442

0.0

0.267

MMV688279

0.0

0.267

MMV687762

0.0

0.267

MMV676480

0.0

0.267

MMV687765

0.0

0.267

MMV000062

0.0

0.267

MMV1110498

0.0

0.267

MMV687700

0.0

0.267

MMV687798

0.0

0.267

MMV024114

0.0

0.267

MMV687796

0.0

0.267

MMV676526

0.0

0.2

MMV102872

0.0

0.2

MMV676386

0.0

0.2

MMV031011

0.0

0.2

MMV020517

0.0

0.2

MMV1030799

0.0

0.2

MMV011691

0.0

0.2

MMV675993

0.0

0.2

MMV676528

0.0

0.2

MMV688889

0.0

0.2

MMV019234

0.0

0.2

MMV688360

0.0

0.2

MMV676600

0.0

0.2

MMV690028

0.0

0.2

MMV688891

0.0

0.2

MMV687696

0.0

0.2

MMV676536

0.0

0.2

MMV671636

0.0

0.2

MMV688980

0.0

0.2

MMV020670

0.0

0.2

MMV687800

0.0

0.2

MMV000023

0.0

0.2

MMV019807

0.0

0.2

MMV024937

0.0

0.2

MMV020391

0.0

0.2

MMV688943

0.0

0.2

MMV676384

0.0

0.2

MMV687776

0.0

0.2

MMV022236

0.0

0.2

MMV024311

0.0

0.2

MMV099637

0.0

0.2

MMV676477

0.0

0.2

MMV688776

0.0

0.2

MMV023949

0.0

0.2

MMV688273

0.0

0.2

MMV688755

0.0

0.2

MMV676182

0.0

0.2

MMV024101

0.0

0.2

MMV676053

0.0

0.133

MMV146306

0.0

0.133

MMV1198433

0.0

0.133

MMV688793

0.0

0.133

MMV020321

0.0

0.133

MMV007133

0.0

0.133

MMV024406

0.0

0.133

MMV202458

0.0

0.133

MMV688553

0.0

0.133

MMV676472

0.0

0.133

MMV019790

0.0

0.133

MMV688274

0.0

0.133

MMV006901

0.0

0.133

MMV688410

0.0

0.133

MMV676589

0.0

0.133

MMV688471

0.0

0.133

MMV020165

0.0

0.133

MMV023985

0.0

0.133

MMV676204

0.0

0.133

MMV1236379

0.0

0.133

MMV676191

0.0

0.133

MMV688766

0.0

0.133

MMV676350

0.0

0.133

MMV676380

0.0

0.133

MMV009054

0.0

0.133

MMV688467

0.0

0.133

MMV019087

0.0

0.133

MMV024443

0.0

0.133

MMV688934

0.0

0.133

MMV688853

0.0

0.133

MMV690027

0.0

0.133

MMV020388

0.0

0.133

MMV1028806

0.0

0.133

MMV688557

0.0

0.133

MMV687254

0.0

0.133

MMV028694

0.0

0.133

MMV026490

0.0

0.133

MMV676406

0.0

0.133

MMV688466

0.0

0.133

MMV689061

0.0

0.133

MMV023388

0.0

0.133

MMV010576

0.0

0.133

MMV688179

0.0

0.133

MMV688852

0.0

0.133

MMV687730

0.0

0.133

MMV676439

0.0

0.133

MMV688936

0.0

0.133

MMV676159

0.0

0.133

MMV689758

0.0

0.133

MMV023969

0.0

0.133

MMV000063

0.0

0.133

MMV658993

0.0

0.133

MMV084603

0.0

0.133

MMV688411

0.0

0.133

MMV153413

0.0

0.133

MMV688417

0.0

0.133

MMV676382

0.0

0.133

MMV010545

0.0

0.133

MMV032967

0.0

0.133

MMV1029203

0.0

0.133

MMV010764

0.0

0.133

MMV687248

0.0

0.133

MMV006372

0.0

0.133

MMV688798

0.0

0.133

MMV689243

0.0

0.133

MMV690102

0.0

0.133

MMV687729

0.0

0.133

MMV676398

0.0

0.133

MMV023860

0.0

0.133

MMV688122

0.0

0.133

MMV690103

0.0

0.133

MMV030734

0.0

0.133

MMV688543

0.0

0.133

MMV676605

0.0

0.133

MMV688470

0.0

0.133

MMV676599

0.0

0.133

MMV676050

0.0

0.133

MMV023370

0.0

0.133

MMV688978

0.0

0.133

MMV688469

0.0

0.133

MMV001625

0.0

0.133

MMV687251

0.0

0.133

MMV687794

0.0

0.133

MMV687273

0.0

0.133

MMV687807

0.0

0.067

MMV228911

0.0

0.067

MMV200748

0.0

0.067

MMV676509

0.0

0.067

MMV688955

0.0

0.067

MMV676474

0.0

0.067

MMV676554

0.0

0.067

MMV687243

0.0

0.067

MMV688472

0.0

0.067

MMV020081

0.0

0.067

MMV676470

0.0

0.067

MMV687188

0.0

0.067

MMV407834

0.0

0.067

MMV688942

0.0

0.067

MMV020982

0.0

0.067

MMV023953

0.0

0.067

MMV007471

0.0

0.067

MMV188296

0.0

0.067

MMV688554

0.0

0.067

MMV026468

0.0

0.067

MMV007920

0.0

0.067

MMV016136

0.0

0.067

MMV022478

0.0

0.067

MMV676597

0.0

0.067

MMV024035

0.0

0.067

MMV053220

0.0

0.067

MMV676161

0.0

0.067

MMV688407

0.0

0.067

MMV006741

0.0

0.067

MMV019838

0.0

0.067

MMV676584

0.0

0.067

MMV007803

0.0

0.067

MMV688958

0.0

0.067

MMV676260

0.0

0.067

MMV688795

0.0

0.067

MMV688762

0.0

0.067

MMV676063

0.0

0.067

MMV676064

0.0

0.067

MMV019721

0.0

0.067

MMV020320

0.0

0.067

MMV020289

0.0

0.067

MMV688474

0.0

0.067

MMV032995

0.0

0.067

MMV688704

0.0

0.067

MMV688372

0.0

0.067

MMV688547

0.0

0.067

MMV022029

0.0

0.067

MMV687170

0.0

0.067

MMV019993

0.0

0.067

MMV687138

0.0

0.067

MMV676461

0.0

0.067

MMV676555

0.0

0.067

MMV688844

0.0

0.067

MMV688796

0.0

0.067

MMV012074

0.0

0.067

MMV676412

0.0

0.067

MMV688854

0.0

0.067

MMV676377

0.0

0.067

MMV688416

0.0

0.067

MMV688797

0.0

0.067

MMV676539

0.0

0.067

MMV688178

0.0

0.067

MMV495543

0.0

0.067

MMV676057

0.0

0.067

MMV676512

0.0

0.067

MMV023183

0.0

0.067

MMV688352

0.0

0.067

MMV667494

0.0

0.067

MMV688991

0.0

0.067

MMV009135

0.0

0.067

MMV069458

0.0

0.067

MMV1037162

0.0

0.067

MMV687706

0.0

0.067

MMV595321

0.0

0.067

MMV688364

0.0

0.067

MMV024195

0.0

0.067

MMV020623

0.0

0.067

MMV085499

0.0

0.067

MMV1019989

0.0

0.067

MMV020136

0.0

0.067

MMV553002

0.0

0.067

MMV688761

0.0

0.067

MMV688941

0.0

0.067

MMV687775

0.0

0.067

MMV085071

0.0

0.067

MMV661713

0.0

0.067

MMV688180

0.0

0.067

MMV687172

0.0

0.067

MMV001059

0.0

0.067

MMV688124

0.0

0.067

MMV688514

0.0

0.067

MMV687145

0.0

0.067

MMV688361

0.0

0.067

MMV688548

0.0

0.067

MMV011765

0.0

0.067

MMV687246

0.0

0.067

MMV688415

0.0

0.067

MMV560185

0.0

0.067

MMV676358

0.0

0.067

MMV000016

0.0

0.067

MMV689255

0.0

0.067

MMV023233

0.0

0.067

MMV001499

0.0

0.067

MMV688990

0.0

0.067

MMV676379

0.0

0

MMV676449

0.0

0

MMV688938

0.0

0

MMV676445

0.0

0

MMV020152

0.0

0

MMV020512

0.0

0

MMV675996

0.0

0

MMV688771

0.0

0

MMV002529

0.0

0

MMV689029

0.0

0

MMV687189

0.0

0

MMV007638

0.0

0

MMV676431

0.0

0

MMV675994

0.0

0

MMV392832

0.0

0

MMV272144

0.0

0

MMV675995

0.0

0

MMV676395

0.0

0

MMV676388

0.0

0

MMV689028

0.0

0

MMV023227

0.0

0

MMV020120

0.0

0

MMV011511

0.0

0

MMV062221

0.0

0

MMV676411

0.0

0

MMV676444

0.0

0

MMV084864

0.0

0

MMV001561

0.0

0

MMV687747

0.0

0

MMV063404

0.0

0

MMV016838

0.0

0

MMV688552

0.0

0

MMV688330

0.0

0

MMV676468

0.0

0

MMV634140

0.0

0

MMV637229

0.0

0

MMV676383

0.0

0

MMV652003

0.0

0

MMV687239

0.0

0

MMV000907

0.0

0

MMV676877

0.0

0

MMV676520

0.0

0

MMV024397

0.0

0

MMV688774

0.0

0

MMV676048

0.0

0

MMV676389

0.0

0

MMV676409

0.0

0

MMV676492

0.0

0

MMV393144

0.0

0

MMV006833

0.0

0

MMV676524

0.0

0

MMV688768

0.0

0

MMV689244

0.0

0

MMV688773

0.0

0

MMV658988

0.0

0

MMV085210

0.0

0

MMV004168

0.0

0

MMV007625

0.0

0

MMV020537

0.0

0

MMV688763

0.0

0

MMV026550

0.0

0

MMV003270

0.0

0

MMV676476

0.0

0

MMV659010

0.0

0

MMV675969

0.0

0

MMV688939

0.0

0

MMV045105

0.0

0

MMV688125

0.0

0

MMV085230

0.0

0

MMV687146

0.0

0

MMV011229

0.0

0

MMV688555

0.0

0

MMV688888

0.0

0

MMV026020

0.0

0

MMV689060

0.0

0

MMV688846

0.0

0

MMV054312

0.0

0

MMV689480

0.0

0

MMV676881

0.0

0

MMV019742

0.0

0

MMV688283

0.0

0

MMV676501

0.0

0

MMV008439

0.0

0

MMV676558

0.0

0

MMV659004

0.0

0

MMV676602

0.0

0

MMV000858

0.0

0

MMV021013

0.0

0

MMV026356

0.0

0

MMV676401

0.0

0

MMV688345

0.0

0

MMV688262

0.0

0

MMV020291

0.0

0

MMV026313

0.0

0

MMV002816

0.0

0

MMV002817

0.0

0

MMV687801

0.0

0

MMV393995

0.0

0

MMV676588

0.0

0

Synthesis of 5-chloro-3-(2,4-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (AEW 276-2)

 

Crude AEW 272-2 (6.12 g, 20.3 mmol, 1 equiv.) was dissolved in anhdrous CH­2Cl2 (203 mL) and (diacetoxyiodo)benzene (6.60 g, 20.3 mmol, 1 equiv.) was added. The reaction mixture was stirred at rt for 3 h and then quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate. Aqueous layers were separated and then extracted with CH­2Cl2 and then organic layers were combined and washed with brine (× 1), dried (MgSO4), filtered and evaporated. The crude mixture was then purified by

NMR

 

Hazard and Risk Assesment:


Strings:


InChI=1S/C11H7Cl3N4/c12-8-2-1-7(3-9(8)13)4-16-18-11-6-15-5-10(14)17-11/h1-6H,(H,17,18)/b16-4+

to

InChI=1S/C11H5Cl3N4/c12-7-2-1-6(3-8(7)13)11-17-16-10-5-15-4-9(14)18(10)11/h1-5H

ClC1=CN=CC(N/N=C/C2=CC(Cl)=C(Cl)C=C2)=N1

to

ClC1=CN=CC2=NN=C(C3=CC(Cl)=C(Cl)C=C3)N21

Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-x)

Repeat of Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-1), see also Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-2) and Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-3)

 

2,6-dichloropyrazine (21 g, 141 mmol, 1 eq) was dissolved in EtOH (282 mL, 0.50 M), and hydrazine hydrate (13.5 mL, 270 mmol, 2 eq) added. The reaction mixture was stirred at reflux for 8 hours.

The solvent was removed under reduced pressure to give a pale yellow solid. Water (~150 mL) and EtOAc (~200 mL) were added, and the mixture was shaken in an attempt to dissolve all solid. The organic layer was removed, the aqueous layer extracted with EtOAc (3 x 100 mL), and the combined organic layers washed with brine (~30 mL) before being concentrated under reduced pressure to yield a yellow solid 

Data:

Crude 300 MHz Data:

AEW 85.pdf
AEW 85.zip

Hazard and Risk Assessment:

See Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-1)

InChi Strings:

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H

to

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

Synthesis of (E)-2-chloro-6-(2-(4-chlorobenzylidene)hydrazineyl)pyrazine (AEW x-x)

Apologies this lab experiment was performed on Thurs/Fri 4/5th May

Outcome:

Obtained the desired product in quantitative yields. NMR Spectra to be uploaded asap.

Reason for Experiment: Synthesised for SSP Class 2017

 

Scheme:

 

Procedure:


AEW 85 (5.00 g, 34.6 mmol, 1.00 equiv.) was dissolved in EtOH (346 mL) and then 4-chlorobenzaldehyde (4.86 g, 34.6 mmol, 1.00 equiv.) was added. The brown/orange soln. was stirred for ten minutes at room temperature. A pale brown solid crashed out of the reaction mixture. The reaction was stirred for a further 2 h and then progress monitored by TLC (10% EtOAc in Hexane) - reaction complete.

Solid filtered under vacuum to give a pale yellow solid 9.8 g, that was dried at the high vac to yield a pale beige/brown powder in quantitative yield. Used as crude in following SSP reactions without NMR evaluation

Hazard and Risk Assessment:

HIRAC SSP OSDD Prac 1 2016.doc

Data:

TLC at 40 min (10% EtoAc in Hexane)

AEW 273-1 (10% EtoAc in Hex).JPG

NMR

Strings:

ClC1=CN=CC(N/N=C/C2=CC=C(Cl)C=C2)=N1

to

ClC1=CN=CC2=NN=C(C3=CC=C(Cl)C=C3)N21

 

InChI=1S/C11H8Cl2N4/c12-9-3-1-8(2-4-9)5-15-17-11-7-14-6-10(13)16-11/h1-7H,(H,16,17)/b15-5+

to

InChI=1S/C11H6Cl2N4/c12-8-3-1-7(2-4-8)11-16-15-10-6-14-5-9(13)17(10)11/h1-6H

Synthesis of (E)-2-chloro-6-(2-(2,4-dichlorobenzylidene)hydrazineyl)pyrazine (AEW 273-2)

Apologies this lab experiment was performed on Thurs/Fri 4/5th May

Outcome:

Obtained the desired product in quantitative yields. NMR Spectra to be uploaded asap.

Reason for Experiment: Synthesised for SSP Class 2017

 

Scheme:

 

Procedure:


AEW 85 (5.00 g, 34.6 mmol, 1.00 equiv.) was dissolved in EtOH (346 mL) and then 2,4-dichlorobenzaldehyde (6.05 g, 34.6 mmol, 1.00 equiv.) was added. The brown/orange soln. was stirred for ten minutes at room temperature. A pale brown solid crashed out of the reaction mixture. The reaction was stirred for a further 2 h and then progress monitored by TLC (10% EtOAc in Hexane) - reaction complete.

Solid filtered under vacuum to give a pale brown solid 11.2 g, that was dried at the high vac to yield a pale beige/brown powder in quantitative yield. Used as crude in following SSP reactions without NMR evaluation

Hazard and Risk Assessment:

HIRAC SSP OSDD Prac 1 2016.doc

Data:

TLC at 40 min (10% EtoAc in Hexane)

AEW 273-1 (10% EtoAc in Hex).JPG

NMR

Strings:

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

and

InChI=1S/C7H4Cl2O/c8-6-2-1-5(4-10)7(9)3-6/h1-4H

to

InChI=1S/C11H7Cl3N4/c12-8-2-1-7(9(13)3-8)4-16-18-11-6-15-5-10(14)17-11/h1-6H,(H,17,18)/b16-4+

ClC1=CN=CC(NN)=N1

and

[H]C(C1=CC=C(Cl)C=C1Cl)=O

to

ClC1=CN=CC(N/N=C/C2=CC=C(Cl)C=C2Cl)=N1