Experimental and theoretical electron density and electrostatic properties as a tool for understanding activity of HIV-1 integrase inhibitor precursors

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Experimental and theoretical electron density and electrostatic properties as a tool for understanding

activity of HIV-1 integrase inhibitor precursors

Delphine Firley, Blandine Courcot, Anne Spasojevic - de Biré, Jean-Michel Gillet, B. Fraisse, Fatima Zouhiri, D. Desmaële, Jean d’Angelo, Pierre J.

Becker, Nour-Eddine Ghermani

To cite this version:

Delphine Firley, Blandine Courcot, Anne Spasojevic - de Biré, Jean-Michel Gillet, B. Fraisse, et al..

Experimental and theoretical electron density and electrostatic properties as a tool for understanding

activity of HIV-1 integrase inhibitor precursors. Gordon Conference, Electron distribution & chemical

bonding, Jul 2004, South Hadley, United States. �hal-02304568�

Electrostatic potential e/Ǻ

1. High resolution X-ray diffraction data Collecte at 100K on a Smart CCD diffractometer 2. Data refinement by the Hansen-Coppens⁽²⁾multipole model

3. Characterization of the chemical bonds and the electrophilic/nucleophilic characters of the two precursors: electron density topological properties and the electrostatic potential 4. Comparaison between the experimental results and the ab initioquantum mechanic calculations for (2)and (3)isolated molecules

5. Theorical calculations for (1) molecule

Experimental and theoretical electron density and electrostatic properties as a tool for understanding activity of HIV-1 integrase inhibitor precursors

D. Firley

^a

, B. Courcot

^a

, A. Spasojevic-de Biré

^a

, J.M. Gillet

^a

, B. Fraisse

^a

, F. Zouhiri

^b

, D. Desmaele

^b

, J. d’Angelo

^b

, P. Becker

^a

and N.E. Ghermani

^a,c

a Laboratoire Structures Propriétés et Modélisation des Solides (SPMS), UMR 8580 CNRS, Ecole Centrale Paris, Grande Voie des Vignes, 92295 Châtenay-Malabry Cedex, France

bBiomolécules: conception, isolement, synthèse (BIOCIS), UMR CNRS 8076, Faculté de Pharmacie de l’Université Paris XI, 5 rue JB Clément, 92296 Châtenay-Malabry Cedex, France

cLaboratoire de Physique Pharmaceutique, UMR CNRS 8612, Faculté de Pharmacie de l’Université XI, 5 rue JB Clément, 92296 Châtenay-Malabry Cedex, France

Styrylquinoline derivatives are potent inhibitors of the HIV-1 virus integrase activity ⁽¹⁾. The biologically tested molecules contain one aromatic part connected to the quinoline group through different chemical spacers. The most promising molecule in the inhibition of the HIV-1 integrase is the (E)-8-hydroxy-2[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) where the spacer is a C=C double bond. The crystallization of this molecule is particularly difficult giving rise to very small needle-shape crystals which are instable in time. In order to recover the molecular property, we have synthesized and crystallized the two precursors of this molecule: the 3’, 4’, 5’-methoxy-dihydroxy benzaldehyde aromatic part (2)and the 8-hydroxy- 7-quinolinic acid (3).

Introduction

Study’s Steps

8-hydroxy-7-quinolinic acid 3’, 4’, 5’-methoxy-dihydroxy benzaldehyde Atomic charges

( ) ( )

ò _{- ¢} ^{¢ ¢}

=

F d r

r r r !

^mol

! r

³

! r !

Electrostatic potential Electrostatic potential

negatif positif

LUMO HOMO

(E)-8-hydroxy-2[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid

u.a. e/Ǻ 0.18319

-0.30167

Crystal environment Crystal environment

Intermolecular hydrogen bonds 1.55 < distance < 2.26Å

Intramolecular Hydrogen bonds

2.21 < distance < 2.61 Å Intermolecular Hydrogen bond

1.83 < distance < 2.36Å

Deformation density

Deformation density

e/Ǻ

Atomic charges

Kappa refinement C-HelpG Kappa refinement C-HelpG

Topological property

(1)Mekouar, K., Mouscadet, J.F., Desmaële, D., Subra, F., Leh, H., Savouré, D., Auclair, C. & d’Angelo, J. (1998). J. Med. Chem.41, 2846-2857.

(2)Hansen, N. and Coppens, P. (1978). Acta Cristallogr.A34, 909

y y E H ˆ =

Topological property

+0.12 -0.40

-0.81 +0.93

+0.50 +0.26

+0.21 -0.32 +0.08 +0.14

+0.14

+0.51

+0.40 -0.44 -0.20

-0.65 -0.34

+0.02

+0.06 +0.17

+0.15

-0.78

+0.12

+

N _Me

OH HOOC

OH OH

OCH OCH3

1. Ac2O D 2. Py, H2O Perkin reaction

N OH HOOC

OH OH OCH3

(1)

(2) (3)

-0.60

+0.62

-0.03 -0.30

+0.28

+0.08

+0.43 -0.40 -0.05

-0.58

-0.64 +0.45

+0.06 +0.20

+0.22

+0.06

-0.36

+0.44 -0.01

+0.12

-0.20

+0.25

-0.03

-0.37 +0.41 +0.16 -0.15

+0.02

-0.50 +0.30 -0.15 -0.04

+0.12

+0.42 -0.36

+0.07

Type de liaison r BCP [e.Å^-3] e H [u.a]

< C — N > 2,09 2,09

0,22 0,17

-0,45 -0,45

< C — C >

(cycle) 2,04 1,95

0,25 0,12

-0,44 -0,42

< C12 — C7 >1,72 1,69

0,23 0,03

-0,33 -0,32

< C12 — O > 2,69 2,43

0,13 0,05

-0,69 -0,58 C8 — O3 2,22

2,04 0,14 0,06

-0,50 -0,44

) ( )

(

atom

mol atom

atom

mol

r - å r - r

Î

r r

Intramolecular Hydrogen bond R. A. H. B. 1.51 Å

Type de liaison r BCP [e.Å-3] e H [u.a]

C'7 — O'1 2,77 2,00

0,08 0,00

-0,72 -0,00

< C' — C' >

cycle 2,06 2,00

0,28 0,00

-0,46 -0,00 C'1 — C'7 1,85

2,0 0,19 0,00

-0,38 -0,00 C' — O'4 1,91

2,00 0,11 0,00

-0,38 -0,00 C' — O' 2,04

2,22 0,14 0,00

-0,43 -0,00

y y E Hˆ=

C’

C’

C’

C’

C’

C’1 C’

C’7 O’1

O’

O’

O’4 )

(r (r)

Contour 0.1 e/ų Contour 0.1 e/ų

y y E H ˆ =

C C

C

C C C C

C7

C8 N C12

O

O O3

C

y y E Hˆ=

Contour 0.1 e/ų