Synthesis and Anti-HIV Activity of Aryl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazones as Potent Non-nucleoside Reverse Transcriptase Inhibitors

• Published in: ChemMedChem 2011-12, Vol.6 (12), p.2225-2232
• Main Authors: Ma, Xiao-Dong, Yang, Shi-Qiong, Gu, Shuang-Xi, He, Qiu-Qin, Chen, Fen-Er, De Clercq, Erik, Balzarini, Jan, Pannecouque, Christophe
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; antiviral agents; Binding Sites; Cell Line; Computer Simulation; diarylpyrimidines; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Hydrazines - chemistry; NNRTIs; Protein Structure, Tertiary; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; reverse transcriptase; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; structure-activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201100334

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 EC50 values in the range of 1.7–13.2 nM. Of these compounds, 2‐bromophenyl‐2‐[(4‐cyanophenyl)amino]‐4‐pyrimidinone hydrazone (9 k) displayed the most potent anti‐HIV‐1 activity (EC50=1.7±0.6 nM), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4‐methyl phenyl analogue 9 d (EC50=2.4±0.2 nM, SI=18461) showed broad spectrum HIV inhibitory activity, with EC50 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. Antiviral agents: A series of new diarylpyrimidine (DAPY) derivatives with a ketone hydrazine substituent on the CH2 linker between the pyrimidine nucleus and the phenyl ring were synthesized, and their anti‐HIV activity in MT‐4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild‐type HIV‐1, with EC50 values in the range of 1.7–13.2 nM.