Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme
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- 作者：Marshall L. Morningstar ; Thomas Roth ; David W. Farnsworth ; Marilyn Kroeger Smith ; Karen Watson ; Robert W. Buckheit ; Jr. ; Kalyan Das ; Wanyi Zhang ; Eddy Arnold ; John G. Julias ; Stephen H. Hughes ; Christo
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：August 23, 2007
- 年：2007
- 卷：50
- 期：17
- 页码：4003 - 4015
- 全文大小：348K
- 年卷期：v.50,no.17(August 23, 2007)
- ISSN：1520-4804
文摘
In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitorsthat are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substitutedbenzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole ledto the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2
M, EC50 = 0.44 M, and TC50 
100 against WT). This paper describes how substitution on thebenzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhancedpotency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT providedthe basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivativeswere nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.
M, EC50 = 0.44 M, and TC50 100 against WT). This paper describes how substitution on thebenzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhancedpotency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT providedthe basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivativeswere nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.