Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators.

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, exhibited moderate anti-HIV-1 activity with an EC value of 5.89 μM, which was slightly weaker than the lead compound (EC = 0.75 μM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by with an HIV-2 EC value of 4.52 μM and nearly 5-fold increased potency over anti-HIV-1 (EC = 21.81 μM), equivalent to (EC = 4.16 μM). Furthermore, preferred to bind to the CA hexamer rather than to the monomer, similar to , according to surface plasmon resonance results. Molecular dynamics simulation indicated that and bound at the same site. Additionally, we computationally analyzed the ADMET properties for and . Based on this analysis, and were predicted to have improved drug-like properties and metabolic stability over , and no toxicities were predicted based on the chemotype of and . Finally, the experimental metabolic stability results of in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.