A heterocyclic molecule with significant activity against dengue virus.
There are no specific approved drugs or vaccines for the treatment or prevention of infectious dengue virus and there are very few compounds known that inhibit the replication of this virus. This letter describes the concise synthesis of two uracil-based multifunctional compounds. One of these compounds (1) has strong activity against dengue virus. It also exhibits low activity against a few other RNA viruses, but is highly active against yellow fever virus, a related flavivirus. It is likely that the mechanism of action of the antiviral activity of this compound is through its inhibition of the enzyme, inosine monophosphate dehydrogenase (IMPDH). Molecular modeling studies reveal that the compound can have specific hydrogen bonding interactions with a number of amino acids in the active site of IMPDH, a stacking interaction with the bound natural substrate, IMP, and the ability to interfere with the binding of NAD(+) with IMPDH, prior to the hydration step.
Nair
Vasu
V
Department of Pharmaceutical and Biomedical Sciences and the Center for Drug Discovery, University of Georgia, Athens, GA 30602, USA.
Chi
Guochen
G
Shu
Qingning
Q
Julander
Justin
J
Smee
Donald F
DF
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology
D000998:Antiviral Agents; D006571:Heterocyclic Compounds; D007168:IMP Dehydrogenase