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HIV-1 CA is involved in different stages of the viral replication cycle, performing essential roles in both early (uncoating, reverse transcription, nuclear import, integration) and late events (assembly). Recent efforts have demonstrated HIV-1 CA protein as a prospective therapeutic target for the development of new antivirals. The most extensively studied CA inhibitor, PF-3450074 (PF-74 , discovered by Pfizer), that targets an inter-protomer pocket within the CA hexamer. Herein we reported the design, synthesis, and biological evaluation of a series of 4-phenyl-1 H -1,2,3-triazole phenylalanine derivatives as HIV-1 CA inhibitors based on PF-74 scaffold. Most of the analogues demonstrated potent antiviral activities, among them, the anti-HIV-1 activity of 6a-9 (EC 50 = 3.13 μM) is particularly prominent. The SPR binding assay of selected compounds (6a-9 , 6a-10 , 5b) suggested direct and effective interaction with recombinant CA proteins. The mechanism of action studies also demonstrated that 6a-9 displays the effects in both the early and late stages of HIV-1 replication. To explore the potential binding mode of the here presented analogues, 6a-9 was analyzed by MD simulation to predict its binding to the active site of HIV-1 CA monomer. In conclusion, this novel series of antivirals can serve as a starting point for the development of a new generation of HIV-1 treatment regimen and highlights the potentiality of CA as a therapeutic target. Image 1 • 4-Phenyl-1 H -1,2,3-triazole phenylalanine derivatives as HIV-1 CA inhibitors were first reported. • 6a-9 showed the best anti-HIV-1 activity among this series. • 6a-9 exhibited the dual-stage inhibitory activity like the lead PF-74. [ABSTRACT FROM AUTHOR]

A small library containing 3-hydroxyquinazoline-2,4(1 H ,3 H )-dione and 1-hydroxypyrido[2,3- d ]pyrimidin-2(1 H )-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3- d ]pyrimidin-2(1 H )-one derivatives showed remarkable anti-HIV potency with EC 50 values ranging from 0.92 to 26.85 µM. The most active one, IIA-2 , also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3- d ]pyrimidin-2(1 H )-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3- d ]pyrimidin-2(1 H )-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity. [ABSTRACT FROM AUTHOR]

HIV-1 capsid (CA) plays indispensable and multiple roles in the life cycle of HIV-1, become an attractive target in antiviral therapy. Herein, we report the design, synthesis, and mechanism study of a novel series of dimerized phenylalanine derivatives as HIV-1 capsid inhibitors using 2-piperazineone or 2,5-piperazinedione as a linker. The structure-activity relationship (SAR) indicated that dimerized phenylalanines were more potent than monomers of the same chemotype. Further, the inclusion of fluorine substituted phenylalanine and methoxyl substituted aniline was found to be beneficial for antiviral activity. From the synthesized series, Q-c4 was found to be the most potent compound with an EC 50 value of 0.57 μM, comparable to PF74. Interestingly, Q-c4 demonstrated a slightly higher affinity to the CA monomer than the CA hexamer, commensurate with its more significant effect in the late-stage of the HIV-1 lifecycle. Competitive SPR experiments with peptides from CPSF6 and NUP153 revealed that Q-c4 binds to the interprotomer pocket of hexameric CA as designed. Single-round infection assays showed that Q-c4 interferes with the HIV-1 life cycle in a dual-stage manner, affecting both pre-and post-integration. Stability assays in human plasma and human liver microsomes indicated that although Q-c4 has improved stability over PF74 , this kind of inhibitor still requires further optimization. And the results of the online molinspiration software predicted that Q-c4 has desirable physicochemical properties but some properties still have some violation from the Lipinski rule of five. Overall, the dimerized phenylalanines are promising novel platforms for developing future HIV-1 CA inhibitors with considerable potential for optimization. [Display omitted] • HIV-1 capsid plays indispensable roles in the life cycle of HIV-1, and becomes an attractive target in antiviral therapy. • It is imperative to explore novel HIV-1 capsid inhibitor. • Compound Q-c4 is the most potent inhibitor with an EC 50 value of 0.57 μM. [ABSTRACT FROM AUTHOR]