title: Synthesis and anti-HIV activity of aryl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazones as potent non-nucleoside reverse transcriptase inhibitors.
abstract: 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.
authors: Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China.
authors: Xiao-Dong
authors: XD
authors: Ma
authors: Shi-Qiong
authors: SQ
authors: Yang
authors: Shuang-Xi
authors: SX
authors: Gu
authors: Qiu-Qin
authors: QQ
authors: He
authors: Fen-Er
authors: FE
authors: Chen
authors: Erik
authors: E
authors: De Clercq
authors: Jan
authors: J
authors: Balzarini
authors: Christophe
authors: C
authors: Pannecouque
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006834:Hydrazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C029424:hydrazine; D054303:HIV Reverse Transcriptase