Discovery of Thiophene[3,2-<i>d</i>]pyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the Tolerant Region I of NNIBP

Our previous studies led us to conclude that thiophene[3,2-<i>d</i>]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (<i>J. Med. Chem</i>. <b>2016</b>, <i>59</i>, 7991-8007; <i>J. Med. Chem</i>. <b>2017</b>, <i>60</i>, 4424-4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains. All the derivatives exhibited moderate to excellent potency against wild-type (WT) HIV-1 in MT-4 cells. Among them, sulfonamide compounds <b>9b</b> and <b>9d</b> were single-figure-nanomolar inhibitors with EC₅₀ values of 9.2 and 7.1 nM, respectively. Indeed, <b>9a</b> and <b>9d</b> were effective against the whole viral panel except RES056. Notably, both compounds showed potent antiviral activity against K103N (EC₅₀ = 0.032 and 0.070 μM) and E138K (EC₅₀ = 0.035 and 0.045 μM, respectively). Furthermore, <b>9a</b> and <b>9d</b> exhibited high affinity for WT HIV-1 RT (IC₅₀ = 1.041 and 1.138 μM, respectively) and acted as classical NNRT inhibitors (NNRTIs). These results are expected to be helpful in the design of thiophenepyrimidine-based NNRTIs with more potent activity against HIV strains with RT mutations.