tetano
Editor, Senior Moderator
J Org Chem. 2013 Oct 3. [Epub ahead of print]
Exploitation of the Catalytic Site and 150 Cavity for Design of Influenza A Neuraminidase Inhibitors.
Adabala PJ, Legresley EB, Bance N, Niikura M, Pinto BM.
Abstract
We report here the exploitation of the 150-cavity in the active site of influenza A viral neuraminidases for the design of novel C-6 triazole-containing Tamiflu derivatives. A general and convenient synthetic route was developed by utilizing a highly substituted cyclic Baylis-Hillman acetate as an active precursor for azide substitution via suprafacial allylic azide [3,3]-sigmatropic rearrangement. Virus replication inhibitory assays in vitro of these triazole derivatives containing either an amino or guanidino-function indicated that the guanidinium compound showed the higher efficacy against a strain with N2 subtype at a concentration of 2 X 10-5 M, but did not inhibit replication of a strain with N1 subtype even at a concentration of 10-4M. In order to probe the nature of the enzyme-inhibitor interactions, molecular dynamics simulations were performed on complexes of these compounds with different neuraminidase enzymes. The results indicated that the candidate inhibitors occupy both the 150-cavity and catalytic site but with alternating occupancy.
PMID:
24090215
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24090215
Exploitation of the Catalytic Site and 150 Cavity for Design of Influenza A Neuraminidase Inhibitors.
Adabala PJ, Legresley EB, Bance N, Niikura M, Pinto BM.
Abstract
We report here the exploitation of the 150-cavity in the active site of influenza A viral neuraminidases for the design of novel C-6 triazole-containing Tamiflu derivatives. A general and convenient synthetic route was developed by utilizing a highly substituted cyclic Baylis-Hillman acetate as an active precursor for azide substitution via suprafacial allylic azide [3,3]-sigmatropic rearrangement. Virus replication inhibitory assays in vitro of these triazole derivatives containing either an amino or guanidino-function indicated that the guanidinium compound showed the higher efficacy against a strain with N2 subtype at a concentration of 2 X 10-5 M, but did not inhibit replication of a strain with N1 subtype even at a concentration of 10-4M. In order to probe the nature of the enzyme-inhibitor interactions, molecular dynamics simulations were performed on complexes of these compounds with different neuraminidase enzymes. The results indicated that the candidate inhibitors occupy both the 150-cavity and catalytic site but with alternating occupancy.
PMID:
24090215
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24090215