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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. Highly active antiretroviral therapy (HAART). Epivir ( lamivudine ; 3TC) - PowerPoint PPT Presentation
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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
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