Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV‑1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

Two series of new pyridyl-bearing
fused bicyclic analogues designed
to target the dual-tolerant regions of the non-nucleoside reverse
transcriptase inhibitor (NNRTI)-binding pocket were synthesized and
evaluated for their anti-HIV activities. Several compounds, such as 6, 14, 15, 21, 30, and 33, were found to be potent inhibitors
against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant
strains at low nanomolar levels. Detailed structure–activity
relationships were obtained by utilizing the variation of moieties
within the corresponding pharmacophores. In vitro metabolic stability
profiles and some drug-like properties of selected compounds were
assessed, furnishing the preliminary structure–metabolic stability
relationships. Furthermore, molecular modeling studies elucidated
the binding modes of compounds 6, 15, 21, and 30 in the binding pocket of WT, E138K,
K103N, or Y181C HIV-1 RTs. These promising compounds can be used as
lead compounds and warrant further structural optimization to yield
more active HIV-1 inhibitors.