Bioisosteric replacement in the search for antimicrobial agents: design, synthesis and activity of novel 6-(1h-Benzimidazol-2-yl)-1-alkyl-3,5-dimethylthieno[2,3-d]pyrimidine-2,4(1h,3h)-dione derivatives

Authors

DOI:

https://doi.org/10.15587/2519-4852.2025.334881

Keywords:

thienpyrimidine, benzimidazole, alkylation, antimicrobial activity, docking

Abstract

The aim. To apply the concept of bioisosterism for the structural optimization of benzimidazole–thieno[2,3-d]pyrimidine hybrids aimed at developing effective antibacterial agents as potential inhibitors of the bacterial enzyme TrmD.

Materials and Methods. Organic synthesis methods; structure confirmation by ¹H, ¹³C, and HMBC NMR spectroscopy, LC-MS, and elemental analysis. Molecular docking was performed using AutoDock Vina, AutoDockTools 1.5.6, and Discovery Studio Client. Antimicrobial activity was evaluated using the agar diffusion method, and the impact on biofilm formation/disruption was assessed using the crystal violet assay.

Results and Discussion. The bioisosteric modification involved oxidation of the thione group in 3,5-dimethyl-4-oxo-2-thioxothieno[2,3-d]pyrimidine-6-carboxylate. The resulting 2,4-dioxothieno[2,3-d]pyrimidine-6-carboxylic acid was activated with 1,1′-carbonyldiimidazole to form a benzimidazole fragment in a one-pot procedure. Alkylation of the obtained hybrid with chloroacetamides led to regioselective products confirmed by HMBC. All synthesized compounds demonstrated significant antimicrobial activity against both Gram-positive and Gram-negative test strains. Compound 5c with a 4-ethoxyphenyl substituent processed the highest activity, including effectiveness against clinical strains of S. aureus and P. aeruginosa. Compound 5c also demonstrated notable biofilm disruption capacity against S. aureus, E. coli, P. aeruginosa, and C. albicans. Molecular docking to the TrmD bacterial enzyme confirmed the formation of a hydrogen bond between the 2-oxo group and Glu121.

Conclusions. An efficient method was developed for the synthesis of a novel series of 2-[6-(1H-benzimidazol-2-yl)-3,5-dimethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]-N-arylacetamides. Bioisosteric hybrids showed enhanced antimicrobial properties and improved binding affinity to bacterial TrmD. Compound 5c demonstrated high activity against both Gram-positive and Gram-negative strains, including clinical isolates, as well as the ability to disrupt biofilms, highlighting its potential as a promising lead for further development

Supporting Agency

  • The research was funded by the Ministry of Health Care of Ukraine at the expense of the State Budget in the framework # 2301020 “Scientific and scientific-technical activity in the field of health protection” on the topic “Synthesis and study of new thienopyrimidines for the detection of antimicrobial and related types of pharmacological activity” (Order of the Ministry of Health of Ukraine of November 17, 2020 No. 2651).

Author Biographies

Sergiy Vlasov, Taras Shevchenko National University of Kyiv; Enamine Ltd.

Doctor of Pharmaceutical Sciences, Professor

Department of Supramolecular Chemistry

Hanna Severina, National University of Pharmacy

Doctor of Pharmaceutical Science, Professor

Department of Pharmaceutical Chemistry

Oleksandr Borysov, Institute of Organic Chemistry of National Academy of Sciences of Ukraine; Enamine Ltd.

PhD, Senior Researcher

Department of Medicinal Chemistry

Georgiy Yakovenko, Taras Shevchenko National University of Kyiv; Enamine Ltd.

PhD

Chemical Faculty

Andrii Khairulin, Taras Shevchenko National University of Kyiv; Enamine Ltd.

PhD

Chemical Faculty

Pavlo Shynkarenko, Enamine Ltd.

PhD

Roman Rudenko, Taras Shevchenko National University of Kyiv; Enamine Ltd.

PhD

Chemical Faculty

Vladimir Bozhanov, Institute of Organic Chemistry of National Academy of Sciences of Ukraine; Enamine Ltd.

PhD

Department of Medicinal Chemistry

Nataliia Smielova, National University of Pharmacy

PhD

Department of Pharmaceutical Chemistry

Nataliia Filimonova, National University of Pharmacy

Doctor of Medical Sciences, Professor

Department of Clinical Laboratory Diagnostics, Microbiology and Biological Chemistry

Victoriya Georgiyants, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor, Head of Department

Department of Pharmaceutical Chemistry

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Bioisosteric replacement in the search for antimicrobial agents: design, synthesis and activity of novel 6-(1h-Benzimidazol-2-yl)-1-alkyl-3,5-dimethylthieno[2,3-d]pyrimidine-2,4(1h,3h)-dione derivatives

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Published

2025-08-30

How to Cite

Vlasova, O., Vlasov, S., Severina, H., Borysov, O., Yakovenko, G., Khairulin, A., Shynkarenko, P., Rudenko, R., Bozhanov, V., Smielova, N., Filimonova, N., & Georgiyants, V. (2025). Bioisosteric replacement in the search for antimicrobial agents: design, synthesis and activity of novel 6-(1h-Benzimidazol-2-yl)-1-alkyl-3,5-dimethylthieno[2,3-d]pyrimidine-2,4(1h,3h)-dione derivatives. ScienceRise: Pharmaceutical Science, (4 (56), 43–55. https://doi.org/10.15587/2519-4852.2025.334881

Issue

No. 4 (56) (2025)

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Pharmaceutical Science

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Copyright (c) 2025 Olena Vlasova, Sergiy Vlasov, Hanna Severina, Oleksandr Borysov, Georgiy Yakovenko, Andrii Khairulin, Pavlo Shynkarenko, Roman Rudenko, Vladimir Bozhanov, Nataliia Smielova, Nataliia Filimonova, Victoriya Georgiyants

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