Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV‑1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel

Our
previous efforts have led to the development of two potent
NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and
resistance profiles compared with etravirine. However, both inhibitors
suffered from potent hERG inhibition and short half-life. In this
article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted
diarylpyrimidine derivatives were designed via molecular hybridization
and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity
(EC50 = 3.60–21.5 nM) against resistant strains,
significantly lower cytotoxicity (CC50= 155 μM),
and reduced hERG inhibition (IC50 > 30 μM). Crystallographic
studies confirmed the binding of 24b and the role of
the fluorine atom, as well as optimal contacts of a nitrile group
with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the
results demonstrated that 24b has significant promise
in circumventing drug resistance as an anti-HIV-1 candidate.