title: Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors.
abstract: This article reports the design, synthesis and antiviral evaluation of a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for their in vitro anti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50 values in the range of 0.0175-69.21 μM. 2-(4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC50 value of 1.75 nM, which was 47 fold lower than that of AZT. Compound 1d also showed a broad-spectrum inhibitory activity, with an IC50 value of 5.33 μM and 5.05 μM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure-activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed.
authors: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: mengge@mail.xjtu.edu.cn.
authors: Ge
authors: G
authors: Meng
authors: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors: Yang
authors: Y
authors: Liu
authors: School of Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, PR China.
authors: Aqun
authors: A
authors: Zheng
authors: Department of Chemistry, Fudan University, Shanghai 200433, PR China. Electronic address: rfchen@fudan.edu.cn.
authors: Fener
authors: F
authors: Chen
authors: Department of Chemistry, Fudan University, Shanghai 200433, PR China.
authors: Wenxue
authors: W
authors: Chen
authors: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors: Erik
authors: E
authors: De Clercq
authors: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors: Christophe
authors: C
authors: Pannecouque
authors: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors: Jan
authors: J
authors: Balzarini
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; 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: D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C030986:pyrimidine
keywords: Cyanide group; Diarylpyrimidines; Docking analysis; Double mutant HIV-1; Non-nucleoside HIV RT inhibitors; SAR