Discovery of Amino Acid-Functionalized Multisubstituted Pyrimidines as Novel Efficient Antiviral Agents Against Enteroviruses

As viral infectious diseases increasingly threaten global health, antiviral drug research has become a crucial focus in medicinal chemistry, especially enteroviruses are common in summer and autumn, with few specific treatments available. Amino acids are essential for protein formation and biological processes. Novel multisubstituted pyrimidine derivatives with amino acid units were designed and synthesized to evaluate their antiviral effects against EV71 and CVB3. Compound <b>8d</b> showed anti-EV71 activity (EC₅₀ = 12.86 ± 0.61 μM), while compound <b>8e</b> was highly active against CVB3 (EC₅₀ = 11.72 ± 1.01 μM), which primarily acted during the replication stage post-EV71 infection. Although it did not directly inhibit key viral proteases like 2Apro, 3Cpro, and 3Dpol, it activated the expression of genes related to the cellular type I interferon signaling pathway, enhancing the host's antiviral defense, which suggests a unique antiviral mechanism. Our research on amino acid-functionalized pyrimidines has clarified their structure-activity relationships, offering a basis for developing new antiviral drugs.