Structure-Based Optimization of Thiophene[3,2‑<i>d</i>]pyrimidine Derivatives as Potent HIV‑1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants

This work follows on from our initial discovery of a series of piperidine-substituted thiophene­[3,2-<i>d</i>]­pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) (J. Med. Chem. 2016, 59, 7991−8007). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound <b>25a</b> was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure–activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that <b>25a</b> is a promising new drug candidate for treatment of HIV-1 infection