Synthesis and Anti-HIV Activity of Aryl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazones as Potent Non-nucleoside Reverse Transcriptase Inhibitors
| Autor: | Qiu-Qin He, Fen-Er Chen, Erik De Clercq, Shi-Qiong Yang, Xiao-Dong Ma, Jan Balzarini, Shuang-Xi Gu, Christophe Pannecouque |
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| Rok vydání: | 2011 |
| Předmět: |
Pyrimidine
Stereochemistry Substituent Hydrazone Biochemistry Cell Line Nucleoside Reverse Transcriptase Inhibitor Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Structure–activity relationship Moiety Computer Simulation General Pharmacology Toxicology and Pharmaceutics Diarylpyrimidines Pharmacology chemistry.chemical_classification Binding Sites Aryl Organic Chemistry HIV Reverse Transcriptase Protein Structure Tertiary Hydrazines Pyrimidines Amino Acid Substitution chemistry HIV-1 Reverse Transcriptase Inhibitors Molecular Medicine |
| Zdroj: | ChemMedChem. 6:2225-2232 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201100334 |
| Popis: | A series of novel diarylpyrimidines (DAPYs) with a ketone hydrazone substituent on the methylene linker between the pyrimidine nucleus and the aryl moiety at the C-4 position were synthesized, and their antiviral activity against human immunodeficiency virus (HIV)-1 in MT-4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild-type HIV-1, with EC(50) values in the range of 1.7-13.2 nM. Of these compounds, 2-bromophenyl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazone (9k) displayed the most potent anti-HIV-1 activity (EC(50) =1.7±0.6 nM), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4-methyl phenyl analogue 9d (EC(50) =2.4±0.2 nM, SI=18461) showed broad spectrum HIV inhibitory activity, with EC(50) values of 2.4±0.2 nM against wild-type HIV-1, 5.3±0.4 μM against HIV-1 double-mutated strain RES056 (K103N+Y181C), and 5.5 μM against HIV-2 ROD strain. Furthermore, structure-activity relationship (SAR) data and molecular modeling results for these compounds are also discussed. |
| Databáze: | OpenAIRE |
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