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The AIDS pandemic is still of importance. HIV-1 and HIV-2 are the causative agents of this pandemic, and in the absence of a viable vaccine, drugs are continually required to provide quality of life for infected patients. The HIV capsid (CA) protein performs critical functions in the life cycle of HIV-1 and HIV-2, is broadly conserved across major strains and subtypes, and is underexploited. Therefore, it has become a therapeutic target of interest. Here, we report a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators. Compound <b>FTC-2</b> is the most potent anti-HIV-1 compound in the new series of compounds, with acceptable cytotoxicity in MT-4 cells (selectivity index HIV-1 > 49.57; HIV-2 > 17.08). However, compound <b>TD-1a</b> has the lowest EC₅₀ in the anti-HIV-2 assays (EC₅₀ = 4.86 ± 1.71 μM; CC₅₀<b>=</b> 86.54 ± 29.24 μM). A water solubility test found that <b>TD-1a</b> showed a moderately increased water solubility compared with <b>PF74</b>, while the water solubility of <b>FTC-2</b> was improved hundreds of times. Furthermore, we use molecular simulation studies to provide insight into the molecular contacts between the new compounds and HIV CA. We also computationally predict drug-like properties and metabolic stability for <b>FTC-2</b> and <b>TD-1a</b>. Based on this analysis, <b>TD-1a</b> is predicted to have improved drug-like properties and metabolic stability over <b>PF74</b>. This study increases the repertoire of CA modulators and has important implications for developing anti-HIV agents with novel mechanisms, especially those that inhibit the often overlooked HIV-2.