Authors: DINAR ADRIATY | Hery Suwito | Ni Nyoman Tri Puspaningsih | Adita Ayu Permanasari | Aldise Mareta Nastri | Kazufumi Shimizu
Source: Trends in Sciences (article, 2025-11-01)
Field: Chemistry — Organic Chemistry

In Vitro Antiviral Activity and Molecular Docking Analysis of Dihydropyrimidinone, Chromene and Chalcone Derivatives Against SARS-CoV-2 To identify and develop effective antiviral agents against SARS-CoV-2, research is ongoing in the field of drug discovery. Heterocyclic compounds such as Chalcone, Chromene, and Dihydropyrimidinone (DHPM) derivatives are of particular interest because of their structural diversity, easily synthesized and broad pharmacological activities, including antiviral effects. Therefore, we investigated the potential of these derivatives against SARS-CoV-2 using cell-based assays, supported by in silico studies. Ten synthetic compounds, consist of 4 DHPMs, 2 chromenes, and 4 chalcones were tested for cytotoxicity and antiviral activity in Vero cells infected with a locally isolated SARS-CoV-2 strain (Clade GH, GISAID: EPI_ISL_529965), using a phenotypic screening approach. Moreover, in silico analyses were performed to predict their drug-likeness, including absorption, distribution, metabolism, and excretion properties, using SwissADME. Molecular docking was conducted to evaluate the binding affinity and interactions of compounds with the SARS-CoV-2 main protease (Mpro). Among the tested compounds, S-10 (chromene derivative) and S-12 (DHPM derivative) demonstrated exhibited significant antiviral activity compared to the other tested derivatives (p &lt; 0.05), with IC₅₀ values of 8.52 ± 0.28 µM and 6.19 ± 0.41 µM, and selectivity index (SI) of 158.8 and 309.7, respectively, indicating strong efficacy and high safety margins. In silico ADME suggested favorable drug-likeness profiles without major toxicity alerts. Molecular docking further revealed that both compounds established stable interactions with the SARS-CoV-2 main protease (Mpro), particularly at the catalytic residues His-41 and Cys-145, supporting their in vitro activity. These results suggest their potential as lead compounds for further drug development, supporting the use of integrated phenotypic and computational approaches in the discovery of region-specific antiviral agents. HIGHLIGHTS Two novel compounds (S-10 and S-12) were identified with strong anti-SARS-CoV-2 activity and high selectivity index (SI &gt; 100), compared to the other 8 compounds tested, out of 10 Dihydropyrimidinone, Chromene, and Chalcone derivative candidates, suggesting high efficacy and low cytotoxicity. Phenotypic screening was performed against a locally isolated SARS-CoV-2 strain (Clade GH, Indonesia) provided, direct biological relevance rather than relying solely on predictive models and supporting region-specific therapeutic development. Supplementary in silico analysis (ADME profiling, toxicity prediction, and molecular docking to Mpro) offers, a comprehensive assessment of efficacy, safety, and mechanism of action. GRAPHICAL ABSTRACT In silico ; ADME ; Docking (animal) ; Chalcone ; In vitro ; Cytotoxicity ; Vero cell ; Protease Multicomponent Synthesis of Heterocycles ; Synthesis and biological activity ; Computational Drug Discovery Methods