Design, Synthesis, and Biological Evaluation of Novel 2-(Pyridin-3-yloxy)acetamide Derivatives as Potential Anti-HIV-1 Agents.
Through a structure-based molecular hybridization and bioisosterism approach, a series of novel 2-(pyridin-3-yloxy)acetamide derivatives were designed, synthesized, and evaluated for their anti-HIV activities in MT-4 cell cultures. Biological results showed that three compounds (Ia, Ih, and Ij) exhibited moderate inhibitory activities against wild-type (wt) HIV-1 strain (IIIB ) with EC50 values ranging from 8.18 μm to 41.52 μm. Among them, Ij was the most active analogue possessing an EC50 value of 8.18 μm. To further confirm the binding target, four compounds were selected to implement an HIV-1 RT inhibitory assay. In addition, preliminary structure-activity relationship (SAR) analysis and some predicted physicochemical properties of three active compounds Ia, Ih, and Ij were discussed in detail. Molecular docking studies were also carried out to investigate the binding modes of Ij and the lead compound GW678248 in the binding pocket of RT, which provided beneficial information for further rational design of non-nucleoside reverse transcriptase inhibitors.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, 250012, Shandong, China.
Boshi
B
Huang
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, 250012, Shandong, China.
Xiao
X
Li
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, 250012, Shandong, China.
Peng
P
Zhan
Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, Leuven, B-3000, Belgium.
Erik
E
De Clercq
Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, Leuven, B-3000, Belgium.
Dirk
D
Daelemans
Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, Leuven, B-3000, Belgium.
Christophe
C
Pannecouque
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, 250012, Shandong, China.
Xinyong
X
Liu
D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism
D000081:Acetamides; C506966:GW 678248; D009570:Nitriles; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D054303:HIV Reverse Transcriptase
HIV-1 RT; anti-HIV activity; bioisosterism; molecular hybridization; non-nucleoside reverse transcriptase inhibitors