Synthesis and biological evaluation of novel 6-substituted 5-alkyl-2-(arylcarbonylmethylthio) pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

被引：19

作者：

Wang, Yue-Ping ^{[1
]}

Chen, Fen-Er ^{[1
]}

De Clercq, Erik ^{[2
]}

Balzarini, Jan ^{[2
]}

Pannecouque, Christophe ^{[2
]}

机构：

[1] Fudan Univ, Dept Chem, Shanghai 200433, Peoples R China

[2] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 07期

基金：

中国国家自然科学基金;

关键词：

HIV; NNRTIs; SAR; S-DABOs;

D O I：

10.1016/j.bmc.2008.01.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A novel series of 2-arylcarbonylmethylthio-6-arylmethylpyrimidin-4(3H)-ones have been synthesized and evaluated for in vitro anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC50 range from 8.97 mu M to 0.010 mu M. Among them, the 6-(3,5-dimethylbenzyl) analogue 5p was identified as the most promising compound (EC50 = 0.010 mu M, SI > 31,800) associated with moderate activity against the HIV-1 double mutant RT strain K103N + Y181C. The structure-activity relationships of these new congeners were further discussed. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3887 / 3894

页数：8

共 18 条

[1] Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family
Artico, M
[J]. DRUGS OF THE FUTURE, 2002, 27 (02) : 159 - 175
[2] QUANTITATIVE ASPECTS OF RADICAL ADDITION .3. RELATIVE RATE RATIOS FOR ADDITION OF TRICHLOROMETHYL RADICALS TO SUBSTITUTED STILBENES, PHENANTHRENE, AND TRANS-BETA-METHYLSTYRENE
CADOGAN, JIG
INWARD, PW
[J]. JOURNAL OF THE CHEMICAL SOCIETY, 1962, (10): : 4170 - &
[3] CLAY RJ, 1993, SYNTHESIS-STUTTGART, P290
[4] TETRACYCLIC BENZODIAZEPINES .4. SYNTHESIS OF THE NOVEL BENZO[C]PYRROLO[1,2,3-EF][1,5]BENZODIAZEPINE RING-SYSTEM, AND DERIVATIVES WITH POTENTIAL ANTIPSYCHOTIC ACTIVITY
GLAMKOWSKI, EJ
CHIANG, YL
[J]. JOURNAL OF HETEROCYCLIC CHEMISTRY, 1987, 24 (06) : 1599 - 1604
[5] Nonnucleoside HIV-1 reverse transcriptase inhibitors;: part 3.: Synthesis and antiviral activity of 5-alkyl-2-[(aryl and alkyloxyl-carbonylmethyl)thio]-6-(1-naphthylmethyl) pyrimidin-4(3H)-ones
He, YP
Chen, FN
Yu, XJ
Wang, YP
De Clereq, E
Balzarini, J
Pannecouque, C
[J]. BIOORGANIC CHEMISTRY, 2004, 32 (06) : 536 - 548
[6] Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1.
Hopkins, AL
Ren, JS
Milton, J
Hazen, RJ
Chan, JH
Stuart, DI
Stammers, DK
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (24) : 5912 - 5922
[7] Synthesis and anti-HIV-1 activity evaluation of 5-alkyl-2-alkylthio-6-(arylcarbonyl or α-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors
Ji, Lei
Chen, Fen-Er
De Clercq, Erik
Balzarini, Jan
Pannecouque, Christophe
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (08) : 1778 - 1786
[8] Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines: Novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series
Mai, A
Artico, M
Sbardella, G
Quartarone, S
Massa, S
Loi, AG
DeMontis, A
Scintu, F
Putzolu, M
LaColla, P
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (10) : 1447 - 1454
[9] 5-alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones: Novel potent and selective dihydro-alkoxy-benzyl-oxopyrimidine derivatives
Mai, A
Artico, M
Sbardella, G
Massa, S
Novellino, E
Greco, G
Loi, AG
Tramontano, E
Marongiu, ME
La Colla, P
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (04) : 619 - 627
[10] SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF THIO ANALOGS OF DIHYDROALKOXYBENZYLOXOPYRIMIDINES
MAI, A
ARTICO, M
SBARDELLA, G
MASSA, S
LOI, AG
TRAMONTANO, E
SCANO, P
LACOLLA, P
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (17) : 3258 - 3263

← 1 2 →