Abstract Objective: The aim of this study was to synthesize S-alkylated and hybrid derivatives of 2-phenyl-5,6,7,8-tetrahydroquinazoline-4(3H)-thione, evaluate their antibacterial and antifungal properties, and perform a docking study against four molecular targets: RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 14 (MAPK14), and monoamine oxidase B (MAO-B). Methods: The starting 2-phenyl-5,6,7,8-tetrahydroquinazoline-4(3H)-thione 1 was alkylated with 2-halogen-1-(aryl)ethan-1-ones 2a–2c, N-substituted chloroacetamides 2d–2e, and 4-methoxy-3-chloromethylbenzaldehyde 4 to give S-alkylated derivatives 3a–3e and 5. Compound 5 was further condensed with 2-thioxothiazolidin-4-one 6 to afford quinazoline-thiazolidine hybrid 7, and with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 8 to give quinazoline-benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one hybrid 9. Reaction of 5 with ethyl cyanoacetate 10 and substituted acetophenones 11a–11d yielded chalcones 12a–12e, which were cyclized with benzamidine hydrochloride 13 into quinazoline-pyrimidine hybrids 14a–14b. All compounds were characterized by IR, NMR, and mass spectrometry, and X-ray diffraction (for 5). Antibacterial activity against E. coli and S. aureus and antifungal activity against C. albicans were tested using the agar diffusion method. Molecular docking was performed using AutoDock Vina. Results and Discussion: S-alkylated derivatives 3a–3e showed moderate to good antibacterial and antifungal activity. Compound 3c (3-nitrophenyl) was active against E. coli and C. albicans, while hybrid 7 exhibited pronounced antifungal properties. Chalcones 12b–12e and pyrimidines 14a–14b showed activity against S. aureus. Docking studies revealed that all synthesized compounds bind strongly to RdRp of SARS-CoV-2 with ΔG° values from –7.0 to –9.0 kcal/mol; hybrid 14b showed the highest affinity (ΔG° of –9.4 kcal/mol), comparable to remdesivir (–8.19 kcal/mol). Against EGFR, derivatives 3d–3e displayed ΔG° below –10.0 kcal/mol, while hybrids 14a–14b showed ΔG below –11.0 kcal/mol, surpassing erlotinib and gefitinib and approaching lapatinib (–11.25 kcal/mol). Hybrid 9 demonstrated exceptional binding to MAPK14 with ΔG° of –13.15 kcal/mol, significantly stronger compared to known inhibitors such as dabrafenib and vemurafenib (ΔG° from –7.52 to –10.40 kcal/mol). Against MAO-B, all compounds showed moderate affinity (ΔG° from –6.78 to –8.99 kcal/mol), comparable to clinical inhibitors moclobemide and selegiline. Conclusions: A series of S-alkylated and hybrid derivatives of 2-phenyl-5,6,7,8-tetrahydroquinazoline-4(3H)-thione were synthesized. Several compounds exhibited antibacterial and antifungal activity comparable to reference drugs (furadonin, furazolidone, fluconazole). Docking studies identified hybrids 14a–14b as potent predicted inhibitors of EGFR and hybrid 9 as a highly potent predicted inhibitor of MAPK14, with binding affinities exceeding those of several clinically used drugs. These results justify further biological evaluation, particularly antitumor screening, of the synthesized quinazoline hybrids.

Synthesis, Docking, and Biological Properties of 2-Phenyl-5,6,7,8-tetrahydroquinazoline-4(3H)-thione Derivatives

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发表日期：

2026年6月18日

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M. S. Safaryan,
R. A. Madoyan,
A. G. Sukiasyan,
A. G. Ayvazyan,
A. A. Mnatsakanyan,
M. Yu. Danghyan,
A. A. Hambardzumyan,
A. A. Harutyunyan

摘要

Abstract

Objective: The aim of this study was to synthesize S-alkylated and hybrid derivatives of 2-phenyl-5,6,7,8-tetrahydroquinazoline-4(3H)-thione, evaluate their antibacterial and antifungal properties, and perform a docking study against four molecular targets: RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 14 (MAPK14), and monoamine oxidase B (MAO-B). Methods: The starting 2-phenyl-5,6,7,8-tetrahydroquinazoline-4(3H)-thione 1 was alkylated with 2-halogen-1-(aryl)ethan-1-ones 2a–2c, N-substituted chloroacetamides 2d–2e, and 4-methoxy-3-chloromethylbenzaldehyde 4 to give S-alkylated derivatives 3a–3e and 5. Compound 5 was further condensed with 2-thioxothiazolidin-4-one 6 to afford quinazoline-thiazolidine hybrid 7, and with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 8 to give quinazoline-benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one hybrid 9. Reaction of 5 with ethyl cyanoacetate 10 and substituted acetophenones 11a–11d yielded chalcones 12a–12e, which were cyclized with benzamidine hydrochloride 13 into quinazoline-pyrimidine hybrids 14a–14b. All compounds were characterized by IR, NMR, and mass spectrometry, and X-ray diffraction (for 5). Antibacterial activity against E. coli and S. aureus and antifungal activity against C. albicans were tested using the agar diffusion method. Molecular docking was performed using AutoDock Vina. Results and Discussion: S-alkylated derivatives 3a–3e showed moderate to good antibacterial and antifungal activity. Compound 3c (3-nitrophenyl) was active against E. coli and C. albicans, while hybrid 7 exhibited pronounced antifungal properties. Chalcones 12b–12e and pyrimidines 14a–14b showed activity against S. aureus. Docking studies revealed that all synthesized compounds bind strongly to RdRp of SARS-CoV-2 with ΔG° values from –7.0 to –9.0 kcal/mol; hybrid 14b showed the highest affinity (ΔG° of –9.4 kcal/mol), comparable to remdesivir (–8.19 kcal/mol). Against EGFR, derivatives 3d–3e displayed ΔG° below –10.0 kcal/mol, while hybrids 14a–14b showed ΔG below –11.0 kcal/mol, surpassing erlotinib and gefitinib and approaching lapatinib (–11.25 kcal/mol). Hybrid 9 demonstrated exceptional binding to MAPK14 with ΔG° of –13.15 kcal/mol, significantly stronger compared to known inhibitors such as dabrafenib and vemurafenib (ΔG° from –7.52 to –10.40 kcal/mol). Against MAO-B, all compounds showed moderate affinity (ΔG° from –6.78 to –8.99 kcal/mol), comparable to clinical inhibitors moclobemide and selegiline. Conclusions: A series of S-alkylated and hybrid derivatives of 2-phenyl-5,6,7,8-tetrahydroquinazoline-4(3H)-thione were synthesized. Several compounds exhibited antibacterial and antifungal activity comparable to reference drugs (furadonin, furazolidone, fluconazole). Docking studies identified hybrids 14a–14b as potent predicted inhibitors of EGFR and hybrid 9 as a highly potent predicted inhibitor of MAPK14, with binding affinities exceeding those of several clinically used drugs. These results justify further biological evaluation, particularly antitumor screening, of the synthesized quinazoline hybrids.