Dengue virus (DENV) is a mosquito-borne virus that causes significant diseases including dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and even death. Dengue virus is an endemic in more than 100 countries and infected 100 millions of world population. The reemergence of dengue outbreak demands an effective and efficient treatment, however, neither vaccine nor drug is available to treat this disease. Targeting a specific protein which has a vital role in an orderly life process is recognized as a more rational strategy in drug design. Thus, the NS2B-NS3 protease which is responsible for dengue virus replication and maturation has become a popular target to design a potential anti-dengue agent. In this study, the homology model of DENV2 NS2B/NS3 protease was first screened with compounds from the National Cancer Institute (NCI) Diversity Set 1 in order to search for new potential dengue inhibitors. The compounds were then ranked based on the energy and the top hit compounds were further tested its activity towards DENV2 NS2B/NS3 protease. Four compounds were shown to have IC<sub>50</sub> values from 30 to 100 µM, and among them a diversity0713 which belongs to thioguanine scaffold has been selected for further derivatization and evaluation of their anti-dengue activities. A series of thioguanine derivatives were prepared and evaluated as dengue inhibitors. The biological assay exhibited inhibitory values with IC<sub>50</sub> from 0.38 &gt;1000 µM. The 3D-QSAR pharmacophore was then generated with four features, i.e. hydrogen bond donor, hydrogen bond acceptor, hydrophobic and aromatic features as the search queries for further optimization. It is hoped that these results may provide an insight into a better understanding in designing of novel and more potent dengue inhibitors.

Modeling, synthesis, and biological activities of thioguanine derivatives for Dengue-2 NS2B/NS3 protease

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.