Synthesis, biological activity, and crystal structure of potent nonnucleoside inhibitors of HIV-1 reverse transcriptase that retain activity against mutant forms of the enzyme
| Autor: | Wanyi Zhang, Christopher J. Michejda, Karen M. Watson, Eddy Arnold, John G. Julias, Marilyn B. Kroeger Smith, Thomas Roth, Robert W. Buckheit, Stephen H. Hughes, David W. Farnsworth, Marshall Morningstar, Kalyan Das |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Benzimidazole Stereochemistry Crystallography X-Ray Article chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship chemistry.chemical_classification Binding Sites Reverse-transcriptase inhibitor biology Molecular Structure Wild type Biological activity Reverse transcriptase HIV Reverse Transcriptase Enzyme chemistry Biochemistry Enzyme inhibitor Mutation biology.protein Molecular Medicine Reverse Transcriptase Inhibitors Benzimidazoles medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 50(17) |
| ISSN: | 0022-2623 |
| Popis: | In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 microM, EC50 = 0.44 microM, and TC50/= 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants. |
| Databáze: | OpenAIRE |
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