Difluoromethylbenzoxazole Pyrimidine Thioether Derivatives: A Novel Class of Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

被引：92

作者：

Boyer, Jeremie ^{[1
]}

Arnoult, Eric ^{[2
]}

Medebielle, Maurice ^{[1
]}

Guillemont, Jerome ^{[2
]}

Unge, Johan ^{[3
]}

Jochmans, Dirk ^{[4
]}

机构：

[1] Univ Lyon 1, ICBMS, UMR CNRS UCBL INSA, Equipe Synth Mol Interet Therapeut SMITH, F-69622 Villeurbanne, France

[2] Janssen Cilag Tibotec, Chem Lead Antimicrobial Res, F-27106 Val De Reuil, France

[3] Lund Univ, MAX Lab, SE-22100 Lund, Sweden

[4] Tibotec Virco BVBA, BE-2340 Beerse, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 23期

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; MEDICINAL CHEMISTRY; DESIGN; TETRAKIS(DIMETHYLAMINO)ETHYLENE; ETRAVIRINE; FLUORINE; MUTANT; ROLES;

D O I：

10.1021/jm200766b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, Si) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 2,4 showed a significant EC50 value close to 6.4 nM against HIV-1 IIIB, a moderate EC50 value close to 54 mu M against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC50 > 100 mu M).

引用

页码：7974 / 7985

页数：12

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