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 8d showed anti-EV71 activity (EC50 = 12.86 ±
0.61 μM), while compound 8e 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.