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HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, <b>F₂-7f</b> exhibited moderate anti-HIV-1 activity with an EC₅₀ value of 5.89 μM, which was slightly weaker than the lead compound <b>PF74</b> (EC₅₀ = 0.75 μM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by <b>7f</b> with an HIV-2 EC₅₀ value of 4.52 μM and nearly 5-fold increased potency over anti-HIV-1 (EC₅₀ = 21.81 μM), equivalent to <b>PF74</b> (EC₅₀ = 4.16 μM). Furthermore, <b>F₂-7f</b> preferred to bind to the CA hexamer rather than to the monomer, similar to <b>PF74</b>, according to surface plasmon resonance results. Molecular dynamics simulation indicated that <b>F₂-7f</b> and <b>PF74</b> bound at the same site. Additionally, we computationally analyzed the ADMET properties for <b>7f</b> and <b>F₂-7f</b>. Based on this analysis, <b>7f</b> and <b>F₂-7f</b> were predicted to have improved drug-like properties and metabolic stability over <b>PF74</b>, and no toxicities were predicted based on the chemotype of <b>7f</b> and <b>F₂-7f</b>. Finally, the experimental metabolic stability results of <b>F₂-7f</b> in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that <b>F₂-7f</b> is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.