RESEARCH INTERESTS

3. Total synthesis of bioactive non-natural products

5. Neglected DiseasesDNDi (Drugs for Neglected Diseases initiative)MMV (Medicines for Malaria Venture)

2. Theoretical chemistry: molecular orbital interactions, naturalbond orbital analysis (NBO)

__________________________

First total synthesis of (-)-ericanone

Dias and coworkersTetrahedron Lett. 2013, 54, 980

_______________

______________Total synthesis of (-)-cryptocaryol A

Dias and coworkersOrg. Biomol. Chem. 2015, 13, 3575

____________Dias and coworkersOrg. Lett. 2003, 5, 265

Total synthesis of (-)-pironetin

O

Et

OH

Me

OMe

Me

OH

pironetin

OH

Me

O

MeO

MeH2N

basiliskamide A

O

Ph

O

Me

OH

MeO

MeH2N

Ph

O

basiliskamide B

_________________Total synthesis of (-)-basiliskamides A and B

Dias and coworkersAdv. Synth. Catal. 2008, 350, 1017J. Braz. Chem. Soc. 2010, 21, 2012

Isolated from the aerial parts of Erica cinereaChulia and coworkers

Tetrahedron Lett. 2011, 52, 1597.

Isolation by Gustafson and coworkersfrom plant Cryptocarya sp. in Papua New GuineaJ. Nat. Prod. 2011, 74, 1015

Isolated from marine bacterium PNG-276 off the coast of Papua New Guinea

Andersen and coworkersJ. Nat. Prod. 2002, 65, 1447

Isolated from Streptomyces sp.Kobayashi and cowrokersJ. Antibiot. 1994 47, 697

36

TBDPSO

OH

14 10O

OH

(R)-17

Co(modp)2 (15 mol%)

t-BuOOH, O2, i-PrOH TBDPSO

O14

10

OH

3760 ºC, 24 h

73%

dr > 95:05

Co(modp)2

O O-

O

N

O

2Co

H3C(H2C)13

OTMS

O

OH

TBDPSO6

7

414

16

17

10O

O

CH3

1

MgBr2.Et2O

CH2Cl2, -30 ºC

59%, dr > 95:5

2 steps

9 steps

CH3(CH2)13

O OH

OO

O

CH3

TBDPSO

i. Zn, EtOH

BrCH2CH2Br

Li2CuBr4

80º C, 8 h

ii. HF.py, THF2 days, r.t.

CH3(CH2)13

OH

OO

O

CH3

OH

1414

1617

10

OH

81% (2 steps) goniotrionin

Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738. (Noyori reduction)

Aerssens, M.H.P.J.; van der Heiden, R.; Heus, M.; Brandsma, L. Synth. Comm. 1990, 20, 3421. (alkyne partial reduction)

Inoki, S.; Mukaiyama, T. Chem Lett. 1990, 67. (oxidative cyclization)

J. Org. Chem. 2012, 77, 4046.17 steps

4% overall yield

Isolated from a Vietnamesecollection of Lyngbya majuscula

(marine cyanobacterium)

Isolation: Chlipala, G. E.; Tri, P. H.; Hung, N. V.; Krunic, A.; Shim, S. H.; Soejarto, D. D.; Orjala, J. J. Nat. Prod. 2010, 73, 784.

Position H (ppm) - Synthetic H (ppm) - Natural

H2 2.42 2.26 H3 4.88 4.74

H14 0.92 0.83 H2a’ 2.38 2.35 H2b’ 2.14 2.05

Main differences betweennatural and synthetic nhatrangin A (1H NMR)

Me Me

O OMe

OH

Nhatrangin A

O

Me

OH

HO

HO

O

1

14

2.5 2.4 2.3 2.2 2.1 2.0

Chemical Shift (ppm)

DMSO-d6

2.4

92.4

52.4

42.4

22.4

12.4

02.3

92.3

92.3

72.3

6

2.1

72.1

52.1

42.1

3

Towards the total synthesis of nhatrangin A___________________ Unpublished results

Me Me

O OMe

OH

O

Me

OH

HO

HO

O

1

14

Analog 1

Position H (ppm) – Analog 1 H (ppm) - Natural

H2 2.48 2.26 H3 4.93 4.74

H14 0.96 0.83 H2a’ 2.39 2.35 H2b’ 2.16 2.05

Main differences betweennatural nhatrangin A and analog 1 (1H NMR)

Me Me

O OMe

OHNhatrangin A

O

Me

OH

HO

HO

O

2.5 2.4 2.3 2.2

Chemical Shift (ppm)

1.13 1.090.93

2.14

2.16

2.17

2.19

2.37

2.38

2.40

2.41

2.45

2.46

2.48

2.50

Towards the total synthesis of nhatrangin A___________________

Me Me

O OMe

OH

O

Me

OH

HO

HO

O

1

14

Analog 2

Position H (ppm) – Analog 2 H (ppm) - Natural

H2 2.53 2.26 H3 4.90 4.74

H14 0.98 0.83 H2a’ 2.38 2.35 H2b’ 2.18 2.05

Me Me

O OMe

OHNhatrangin A

O

Me

OH

HO

HO

O

Main differences betweennatural nhatrangin A and analog 2 (1H NMR)

2.6 2.5 2.4 2.3 2.2 2.1

Chemical Shift (ppm)

1.12 1.101.09

2.1

52.1

72.1

82.2

0

2.3

62.3

62.3

92.3

9

2.5

32.5

52.5

6

___________________Towards the total synthesis of nhatrangin A

Me Me

O OMe

OH

O

Me

OH

HO

HO

O

1

14

Analog 3

Position H (ppm) – Analog 3 H (ppm) - Natural

H2 2.47 2.26 H3 4.92 4.74

H14 0.96 0.83 H2a’ 2.39 2.35 H2b’ 2.16 2.05

Me Me

O OMe

OHNhatrangin A

O

Me

OH

HO

HO

O

Main differences betweennatural nhatrangin A and analog 3 (1H NMR)

2.5 2.4 2.3 2.2 2.1

Chemical Shift (ppm)

1.54 1.06 1.06

2.13

2.15

2.16

2.18

2.37

2.38

2.40

2.41

2.44

2.46

2.47

2.49

___________________Towards the total synthesis of nhatrangin A

Position H (ppm) – Analog 4 H (ppm) - Natural

H2 2.54 2.26 H3 5.00 4.74

H14 0.97 0.83 H2a’ 2.44 2.35 H2b’ 2.22 2.05

Me Me

O OMe

OHNhatrangin A

O

Me

OH

HO

HO

O

Main differences betweennatural nhatrangin A and analog 4 (1H NMR)

Me Me

O OMe

OH

O

Me

OH

HO

HO

O

1

14

Analog 4

2.6 2.5 2.4 2.3 2.2 2.1 2.0

Chemical Shift (ppm)

1.071.05 1.00

DMSO-d6

2.5

72.5

62.5

42.5

22.4

92.4

62.4

52.4

32.4

2

2.2

42.2

22.2

12.1

9

___________________Towards the total synthesis of nhatrangin A

Position H (ppm) – Analog 5 H (ppm) - Natural

H2 2.52 2.26 H3 4.81 4.74

H14 0.94 0.83 H2a’ 2.34 2.35 H2b’ 2.14 2.05

Me Me

O OMe

OHNhatrangin A

O

Me

OH

HO

HO

O

Main differences betweennatural nhatrangin A and analog 5 (1H NMR)

Me Me

O OMe

OH

O

Me

OH

HO

HO

O

1

14

Analog 5

2.6 2.5 2.4 2.3 2.2 2.1 2.0

Chemical Shift (ppm)

1.000.99 0.96

DMSO-d6

2.5

52.5

32.5

22.4

9

2.3

72.3

62.3

32.3

2

2.1

82.1

52.1

42.1

2

___________________Towards the total synthesis of nhatrangin A

Posição H (ppm) – Analog 5 H (ppm) - Natural

H2 2,53 2,26 H3 4,98 4,74 H5 1,16 1,23

1,41 H6 1,38 1,60

1,70 H14 0,98 0,83 H15 0,80 0,74 H2a’ 2,44 2,35 H2b’ 2,20 2,05 H3’ 3,70 3,75

2.5 2.4 2.3 2.2 2.1 2.0

Chemical Shift (ppm)

1.04 1.000.92

DMSO-d6

2.5

52.5

42.5

32.5

22.4

92.4

52.4

52.4

32.4

2

2.2

22.2

02.2

02.1

8

Me Me

O OMe

OH

O

Me

OH

HO

HO

O

Analog 6

Main differences betweennatural nhatrangin A and analog 6 (1H NMR)

Me Me

O OMe

OHNhatrangin A

O

Me

OH

HO

HO

O

___________________Towards the total synthesis of nhatrangin A

20Dias, L. C.; de Lucca, E. C., Jr.; Ferreira, M. A. B.; Garcia, D. C.; Tormena, C. F. Org. Lett. 2010, 12, 5056.Dias, L. C.; de Lucca, E. C., Jr.; Ferreira, M. A. B.; Garcia, D. C.; Tormena, C. F. J. Org. Chem. 2012, 77, 1765.

1,3-anti

anti -Felkin

OH

Me

PMBO

Me

Me

O OTBSOO

MeMe

1,5-antiMe

O O OTBSO

MeMe 1) (c-Hex)2BCl, Et3N

Et2O, –30 °C

2) , –78 °C

90%, ds > 95:05

25292533

33 H

O

Me

PMBO

Me

Me

OH

Me

PMBO

Me

Me

O OTBSOO

MeMe

2533

O

Me

PMBO

Me

Me

O OO

MeMeMeMe

S NN

NN

PhOO252933

____________________Sulfone – C23-C35 Fragment

32

LiOH, THFMeOH, H2O, rt

quant.O

Me

OH

Me

Me

O OO

MeMeMeMe

252933 21

O

O

OH

OH

Me

O

MeO

1

13

17 O

Me

OH

Me

Me

O OO

MeMeMeMe

252933 21

O

O

OH

OH

Me

O

OH

1

13

17

Attempts to prepare the desired macrolactone

1) TCBC, Et3NTHF, rt

O

Me

OH

Me

Me

O OO

MeMeMeMe

252933 21

O

O

OH

OH

Me

O

OH

1

13

17 O

Me

O

Me

Me

O OO

MeMeMeMe

252933 21

O

O

OH

OH

Me

O1

13

172) DMAPPhMe, 60 °C

_____________________

Parasitic Tropical Diseases

Public Institutional DonorsPrivate DonorsPrivate Foundations and Private Individual Donors

____________________

www.dndi.org

100 million people at risk in Latin America

Endemic 21 countries in Latin and Central America

8 million infected in Latin America

55.000 new cases per year

Kills more people in region than malaria

GLOBAL VIEW

Approximately 8 million cases, 14,000 deaths per year

430,000 disability-adjusted life years (DALYs) are lost per year

Chagas disease is the leading cause of infectious

cardiomyopathy worldwide

DNDi estimates that less than 1% of the infected people

receive treatment

Chagas Disease

Partnership DNDi and:

LAFEPE – Brazil

Fundacion Mundo Sano And Ministerio SaudeArgentina

ELEA produces ABARAX

• Lead Optimization Latin America (LOLA)

The Lead Optimization Latin America (LOLA)

consortium: collaborative drug discovery for

Neglected Tropical Diseases (NTDs)

Luiz Carlos Dias1, Marco A. Dessoy1, Brian W. Slafer1, Adriano

Andricopulo2, Glaucius Oliva2, Dale Kempf3, Brian Brown3, Mira

Hinman3, Yvonne C. Martin3, Charles E. Mowbray4, Simon F.

Campbell51Instituto de Química – UNICAMP, Campinas, Brazil2Laboratorio de Química Medicinal e Computacional, Centro de Biotecnologia Molecular

Estrutural– USP, São Paulo, Brazil3AbbVie Inc., Chicago, USA

4Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland

5Independent consultant

Design and Analysis of new targetsCollaborative effort by UNICAMP, AbbVie, Simon Campbell & DNDi

SynthesisUNICAMP, Campinas

Primary ParasitologyUSP São Carlos and LMPH, Antwerp

in vitro ADMEAbbvie, Chicago

Secondary ParasitologySwiss Tropical Institute Formulation – in vivo PK

Wuxi AppTech, Shanghai

Mouse model of Chagas DiseaseLSHTM, London

Early screening

cascade & partners

General Synthesis

NH2

S

NC+Me Me

O O

Me NH

Me

CN

S

Et3Nethanol

reflux, 30 min

Schmidt, U.; Kubitzek, H. Chem. Ber. 1960, 93, 1559-1565. TDR30139

analogues

thiopyridone

monocyclic cyanopyridines

Me N

Me

CN

S R3

bicyclic cyanopyridines

NH2

S

NC+

H Ar

O

N O

Et3N, ethanol

reflux, 30 min

then piperidinereflux, 18 h

Bocthiopyridone

NH

N

S

CN

Ar

Boc

NIH lead

analoguesAbdel-Wadood, F. K.; Abdel-Monem, M. I.; Fahmy, A. M.; Geies, A. A. J. Chem. Res. 2008, 89-94.

Synthesis of TDR30139 derivatives

TDR91228

IC50 = 1.2 M

H3C N

CH3

CN

S

S

OH

TDR100612

IC50 = 70 M

H3C N

CH3

CN

O

O

S

TDR30139

IC50 = 0.34 M

H3C N

CH3

CN

S

O

S

LOLA67

IC50 = 0.58 M

SN

CN

CH3

H3C

O

F

N

HN

S

S

CN

HN

O

F

LOLA3

IC50 = 0.31 µM

N

N

S

S

CN

HN

O

F

LOLA4

IC50 = 0.03 µM

N

HN

S

CN

HN

O

LOLA48

IC50 = 7.9 µM

F

HCl

TDR95696

IC50 = 2.0 M

N

CH3

HO

CN

S

O

S

monocyclic

bicyclic

www.mmv.org

Combating malaria with the power of research

Malaria is caused by protozoan parasites of the genus

Plasmodium – single-celled organisms that cannot

survive outside of their host(s). Malaria is the leading

parasitic cause of morbidity and mortality worldwide,

especially in developing countries where it has

serious economic and social costs.

Endemic

Approximately 219 million cases

627 000 deaths per year (91% in Africa)

33.976 000 disability-adjusted life years (DALYs) are lost per year.

Malaria is worldwide the leading parasitic cause of morbidity and mortality

Malaria burden

William C. Campbell, Satoshi Ōmura and Youyou Tu Win 2015 Nobel Prize for Physiology or MedicineAwards: Researchers' work led to drugs against roundworm diseases and malaria

Ivermectin: C&EN’s Top Pharmaceuticals That Changed the World: http://pubs.acs.org/cen/coverstory/83/8325/8325ivermectin.html

MMV project collaborators in alphabetical order and their contribuitons

Abbvie (USA) Robert Schmitt’s group runs assay on human kinases to determine

possible adverse affects of the compounds.

AstraZeneca

(AZ, UK)

in silico predictions of physicochemical and DMPK properties of new

synthetic targets. DMPK and physicochemical property screening.

Monash University – Centre for Drug

Candidate Optimization (CDCO,

Australia)

Prof. Susan Charman´s group. DMPK screening centre for MMV.

in vitro metabolic stability assessment on rat, mouse and human

microsomes and rat hepatocytes. Determination of main metabolites.

Rat and mouse in vivo DMPK experiments to aid selection of compounds

for in vivo efficacy studies and the optimization of DMPK properties.

Biomedical Primate Research Centre

(BPRC, Netherlands)

Prof C. Kochans lab at BPRC acts as MMV`s screening centre to evaluate

compounds activity against hypnozoites (the dormant liver form of

plasmodium vivax) using P. cynomolgi (a non-human primate malaria

parasite).

GlaxoSmithKline (GSK, Spain) in vitro parasite reduction ratio assay (evaluating the compounds rate of

killing of the malaria parasite in vitro).

in vivo blood stage efficacy experiment (SCID mice infected with P.

falciparum, dosed with compound).

Standard Membrane Feeding assay – detailed assessment of transmission

blocking potential.

Imperial College London (UK) MMV's primary screening centre for evaluating compounds

transmission blocking potential.

P. falciparum dual male and female gamete formation assay.

P. falciparum transmission-blocking assay.

Mahidol University

(Thailand)

Prof. Jetsumon Prachumsri’s lab runs the P. vivax in vitro liver assay.

Medicines for Malaria Venture

(MMV, Switzerland)

Financial support of the project.

Providing quality targets from HTS for new series.

Paul Willis manages the team and advices on direction of the projects.

Organization of the biological assays.

Novartis

(Switzerland)

Provided initial homology model for plasmodium PI4K.

Schrödinger (USA) Molecular modelling support. Preparation of homology models and docking of

derivatives to support rational design, as well as prediction of DMPK properies

through the integrated platform of LiveDesign.

Structural Genomics Consortium (SGC,

University of Toronto, Canada)

Co-crystallization of active compounds with their enzyme targets.

Swiss TPH (Switzerland) Public organization which runs a number of malaria screens from MMV including

in vivo efficacy and screening against drug resistant parasites.

Sergio Wittlin is a member of the project team to provide parasitology advice.

Syngene (India) Primary malaria screen evaluating the ability of compounds to kill the erythrocytic

asexual stages of P. falciparum in vitro (IC50 assay on the NF54 and K1 strains. In

vitro Cytotoxicity screen.

MMV project collaborators in alphabetical order and their contribuitons

MMV project collaborators in alphabetical order and their contribuitons

Unicamp (Campinas, Brazil) Prof. L.C. Dias lab runs the project at UNICAMP.

Selection of targets provided by MMV.

Planning and synthesis of derivatives.

Data evaluation and decision on course of the series.

UC San Diego (UCSD, USA) Prof. Elizabeth Winzeler`s lab acts as MMV`s screening centre to evaluate activity

of compounds against the liver stage of the malaria parasite by studying the effect

of the compounds on a hepatic cell line infected with P. berghei.

Simultaneously provides cytotoxicity assessment.

University of Dundee (Scotland, UK) The international centre for kinase profiling provides the screen on 100 human

lipid kinases and runs the human PI3Kα assay to provide information on the

selectivity of our plasmodium PI4K inhibitors.

University of Sao Paulo at Sao Carlos,

Centre for Research and Innovation in

Biodiversity and New Drugs-CIBFAR

(IFSC-USP, Brazi)

The LQMC (Laboratory of Medicinal and Computational Chemistry) conduct

medicinal chemistry studies including in vitro testing of new compounds against P.

falciparum and parallel assessments of cytotoxicity against MRC-5 (human

fibroblast) cells and PMMs (primary mouse macrophages).

The same lab is establishing validated assays to test promising active compounds

in animal models of P. falciparum.

University of Victoria (Uvic, Canada) Prof. John Burke´s lab runs the P. vivax PI4K enzyme assay.

Co-crystallization of active compounds with human PI3Ka

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Evaluated Targets 2013-2014

Molecular Weight 380.40In vitro human/ rodent mics

(Clint µl/min/mg)

17.35 (human mics)

70.42 (mouse mics)

24.33 (rat heps)

LogD for pH 7.4 3.0 Rodent oral bioavailability61% at 5mg/kg

(close derivative)

Whole cell potency (IC50 nM)

(NF54)23

Rodent iv clearance estimated

(Cl ml/min/kg at dose)

59 at 2mg/kg

(close derivative)

Cross resistance (IC50 nM)

(K1, HB3, 7G8, TM80C2B, D6, V1/S,

Db2, FCB)

19-25 Rodent Vd, t1/2 (L/Kg, h)

Cytotoxicity THP1 (µM)>50

(close derivative)

In vivo efficacy Peters 4 day test

(Pb/ Pf ED90 - mg/kg)

In vitro PRR (Log PRR) 3.1 (ATQ like) AUC at ED90 (nM.h)

Exo-erythrocytic stages (Y/N)*Pberghei liver: Y

Pcynomolgi liver: N

In vivo PRR (comparable with which known

antimalarial)

Solubility (µM) 14Cyp inhibition

(3A4, 2C9, 2D6, 1A2, 2C19) IC50 (µM)

Permeability: Human Caco2 AB

pH6.5 (1E-6 cm/s)34.3 hERG IC50 (µM)

>33.3

(close derivative)

Protein binding (human %) >96.3Solubility

studies

Frontrunner profile MMV085400

Confidential

IV - Solution in 60% PEG400, 50 mM sodium citrate, pH 4.5.PO- Solution in 25% hydroxypropyl-b-cyclodextrin, 50 mM sodium citrate, pH 3.3.

• Binding:• Hinge binder: 1 of 3

possible bonds utilized• Extending substituents

into the specificity pocket

• Selectivity:• Introduction of

substitution to exploitdifferences betweenhuman and plasmodiumphosphatidylinositolkinases

• Solubility:• Ligand-site exposed to

solvent can carrysolubilizing groups

Pfizer – La Jolla solved and refined the co-crystal structure of MMV085400 with human PIK3a

X-ray / homology modelStructural Genomics Consortium

SGC – Toronto

Acknowledgements

Brian Brown, Mira Hinman,

Yvonne C. Martin, and Dale Kempf

Glaucius Oliva, Adriano Andricopulo, Marco Dessoy, Pablo

Martinez and Celso Oliveira (+ Paul Koovits – 02-2016)

James Mills

Manu De RyckerMarcel Kaiser

Prof. Louis Maes

An Matheeussen, Margot Desmet

Charlie Mowbray and Simon CampbellWen Hua

Alan Brown

Acknowledgements

Susann Krake, Maitia Labora and Pablo Martinez

Sue Charman

Mark Wenlock, Barry

Jones, and Mark

TimmsSergio Wittlin

Paul Willis, Melanie

Rouillier

and Simon Campbell

Noj Malcom, Thomas

Steinbrecher, Soumya

Ray and Melissa Landon