Synthesis and evaluation of a new series of substituted acyl(thio)urea and thiadiazolo [2,3-a] pyrimidine derivatives as potent inhibitors of influenza virus neuraminidase.
A series of substituted acyl(thio)urea and 2H-1,2,4-thiadiazolo [2,3-a] pyrimidine derivatives were prepared and both of their cell culture and enzymatic activity toward influenza virus were tested. Their in vitro neuraminidase inhibitory activities were in good agreement with the corresponding activities in cultured cells and they were evaluated as potent neuraminidase inhibitors. Of the analogues that demonstrated IC(50)s<0.1microM, 16 and 60 were further investigated as candidates with the most potential for future development. The molecular docking work of the representative compound was described to provide more insight into their mechanism of action and further rationalize the observations of this new series herein, which represents a novel class of highly potent and selective inhibitors of influenza virus.
Sun
Chuanwen
C
Department of Biosynthetic Drugs, School of Pharmacy, Fudan University, Shanghai 200032, China. sunwillin@sjtu.edu.cn
Zhang
Xiaodong
X
Huang
Hai
H
Zhou
Pei
P
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D009439:Neuraminidase; D013890:Thiourea; C030986:pyrimidine