This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]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 25a 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 25a is a promising new drug candidate for treatment of HIV-1 infection.

We report herein the design and synthesis of a series of 11 novel tacrine-1,2,3-triazole derivatives a Cu(i)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. The newly synthesized compounds were evaluated for their inhibition activity against acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) as potential drug targets for Alzheimer's disease (AD). Among the designed compounds, compound exhibited potent inhibition against AChE and BChE with IC values of 4.89 μM and 3.61 μM, respectively. Further structure-activity relationship (SAR) and molecular modeling studies may provide valuable insights into the design of better tacrine-triazole analogues with potential therapeutic applications for AD.

A novel series of diarylpyrimidine derivatives, which could simultaneously occupy the classical NNRTIs binding pocket (NNIBP) and the newly reported "NNRTI Adjacent" binding site, were designed, synthesized, and evaluated for their antiviral activities in MT-4 cell cultures. The results demonstrated that six compounds (, and-) showed excellent activities against wild-type (WT) HIV-1 strain (EC = 2.4-3.8 nM), which were more potent than that of ETV (EC = 4.0 nM). Furthermore, ,, , and showed more potent or equipotent activity against single mutant HIV-1 strains compared to that of ETV. Especially, showed marked antiviral activity, which was 1.5-fold greater against WT and 1.5- to 3-fold greater against L100I, K103N, Y181C, Y188L, and E138K when compared with ETV. In addition, all compounds showed lower toxicity (CC = 5.1-149.2 μM) than ETV (CC = 2.2 μM). The HIV-1 RT inhibitory assay was further conducted to confirm their binding target. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed comprehensively.

Our previous studies led us to conclude that thiophene[3,2-]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (. ,, 7991-8007; ., , 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 and were single-figure-nanomolar inhibitors with EC values of 9.2 and 7.1 nM, respectively. Indeed, and were effective against the whole viral panel except RES056. Notably, both compounds showed potent antiviral activity against K103N (EC = 0.032 and 0.070 μM) and E138K (EC = 0.035 and 0.045 μM, respectively). Furthermore, and exhibited high affinity for WT HIV-1 RT (IC = 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.