NOVEL PYRIMIDINE DERIVATIVES AS NONNUCLEOSIDE INHIBITORS OF HIV REPLICATION

A.V. Ivanov, V.T. Valuev-Elliston, S.N. Kochetkov, C. Pannecouque,

J. Balzarini, K.L. Seley-Radtke, M.S. Novikov

• Epivir (lamivudine; 3TC)

• Emtriva (emtricitabine; FTC)

• Retrovir (zidovudine; AZT)

• Videx (didanosine; ddI)

• Viread (tenofovir)

• Zerit (stavudine; d4T)

• Ziagen (abacavir)

•Viramune (Nevirapine)

•Sustiva (Efavirenz)

•Intelence (Etravirine)

Reverse transcriptase

• Agenerase (amprenavir)

• Crixivan (indinavir)

• Invirase (saquinavir)

• Kaletra (lopinavir/ritronavir)

• Norvir (ritonavir)

• Prezista (darunavir)

• Reyataz (atazanavir)

• Viracept

Isentress (raltegravir)

Protease

Integrase

Selzentry ( maraviroc)

CCR5 рreceptor

Highly active antiretroviral therapy (HAART)Highly active antiretroviral therapy (HAART)

Nevirapine (NVP) Efavirenz (EFV)

Etravirine (ETV)

N NN

NH

OCH3

O

NH

O

ClF3C

N

N

NH

NH2

Br

O

CH3CH3

CN

CN

NH

NH

S

O

O

O

N

N

N

NHDelavirdine (DLV)

N

N

NH

NH

CH3CH3

CN

CN

Rilprivirine (TMC278)

FDA-approved non-nucleoside inhibitors of the FDA-approved non-nucleoside inhibitors of the reverse transcriptase (NNRTI)reverse transcriptase (NNRTI)

NNRTI binding site

G190AP225HM230L

L100IK103NV106A

A number of amino acid substitutions in NNRTI binding site lead to formation of drug resistant HIV strains. These substitutions include:

V179IY181CY188L

Goals of the projectGoals of the project

Synthesis of novel substituted pyrimidines and their evaluation as potential anti-HIV agents

Groups involved

•Synthesis: Volgograd State Medical University (Volgograd, Russia) –

P.I. Dr. M. Novikov.

•Investigation of antiretroviral activity in infected cell cultures: Rega Institute for Medical Research, K.U. Leuven (Leuven, Belgium)

P.I. Prof. J. Balzarini

•Evaluation of the compounds as inhibitors of the wild-type and drug-resistant reverse transcriptases: Engelhardt Institute of Molecular Biology

P.I. Prof. S. Kochetkov

O

R1

N

NH

O O

O

R3

R4

R2

Inhibitor RT HIV-1 (wild type)

№ R1 R2 R3 R4KI

M

EC50*

M

CC50*

M SI

1 4-CH3 3,5- (CH3)2 - - 5,9 0,36 508 1431

2 4-Cl 3,5- (CH3)2 - - 5,0 0,57 >1000 >2273

3 4-Br 3,5- (CH3)2 - - 11 0,51 >1000 >2273

4 Cl 3,5-(CH3)2 H H 2,4 0,025 222 8860

5 Cl 3,5-(Cl)2 H H 0,68 0,027 257 >9417

NVP 7,2 0,06 >100 >1667

EFV 0,01 0,002 35,72 17860

O

R1

N

NH

O O

R2

1-[2-(2-1-[2-(2-BenzylphenoxyBenzylphenoxy))ethyl]pyrimidinesethyl]pyrimidines (1-3) (1-3)1-[2-(2-1-[2-(2-

benzoylphenoxybenzoylphenoxy))ethyl]pyrimidinesethyl]pyrimidines (4-7) (4-7)

1-3

4-7

O

Cl

N

NH

O O

O

Cl

Cl

KI, М

1 2 3 EFV NVP

WT 0,083 2,4 0,7 0,01 7,2

L100I 0,31 3,3 0,86 0,08 273

K103N 4,68 33 5,68 0,58 >2000

V106A >8,3 >240 >70 0,05 >2000

Y181C 0,21 8 0,36 0,03 >2000

G190A 0,37 1 0,9 0,06 >2000

K103N / Y181C 8,56 57 5,76 0,14 >2000

O

Cl

N

NH

O O

O

CH3

CH3

32

Activity against mutant drug-resistant RTsActivity against mutant drug-resistant RTs

Vladimir Valuev-EllistonDr. Alexander Ivanov

Prof. Sergey Kochetkov

Prof. Christophe Pannecouque,Prof. Jan Balzarini

Prof. Katherine Seley-Radtke

Dr. Mikhail Novikov