title: Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs.
abstract: In continuation of our efforts toward identification and optimization of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), we have employed a structure-based bioisosterism strategy, with which a new series of diarylpyridazine (DAPD) derivatives were synthesized and evaluated for their anti-HIV-1 (human immunodeficiency virus type 1) activity. Most of the title compounds displayed excellent anti-HIV-1 activity at submicromolar concentrations ranging from 34 nM to 5.08 μM. The most promising compound 8g inhibited HIV-1 IIIB in MT-4 cells at a low EC50 value (0.034 μM), which was lower than the reference drug nevirapine and delavirdine. The structure activity relationships (SARs) were discussed and rationalized by docking simulations.
authors: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.
authors: Dongyue
authors: D
authors: Li
authors: Peng
authors: P
authors: Zhan
authors: Huiqing
authors: H
authors: Liu
authors: Christophe
authors: C
authors: Pannecouque
authors: Jan
authors: J
authors: Balzarini
authors: Erik
authors: E
authors: De Clercq
authors: Xinyong
authors: X
authors: Liu
mesh_terms: D002460:Cell Line; D020008:Delavirdine / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019829:Nevirapine / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011724:Pyridazines; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D020008:Delavirdine; D054303:HIV Reverse Transcriptase