Discovery of Novel Dihydrothiopyrano[4,3-<i>d</i>]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles

Enlightened by the available structural biology information, a novel series of dihydrothiopyrano[4,3-<i>d</i>]pyrimidine derivatives were rationally designed <i>via</i> scaffold hopping and molecular hybridization strategies. Notably, compound <b>20a</b> yielded exceptionally potent antiviral activities (EC₅₀ = 4.44-54.5 nM) against various HIV-1 strains and improved resistance profiles (RF = 0.5-5.6) compared to etravirine and rilpivirine. Meanwhile, <b>20a</b> exhibited reduced cytotoxicity (CC₅₀ = 284 μM) and higher SI values (SI = 5210-63992). Molecular dynamics simulations were performed to rationalize the distinct resistance profiles. Besides, <b>20a</b> displayed better solubility (sol. = 12.8 μg/mL) and no significant inhibition of the main CYP enzymes. Furthermore, <b>20a</b> was characterized for prominent metabolic stability and <i>in vivo</i> safety properties. Most importantly, the hERG inhibition profile of <b>20a</b> (IC₅₀ = 19.84 μM) was a remarkable improvement. Overall, <b>20a</b> possesses huge potential to serve as a promising drug candidate due to its excellent potency, low toxicity, and favorable drug-like properties.