Synthesis, docking study and antimicrobial activity evaluation of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acid

Authors

DOI:

https://doi.org/10.15587/2519-4852.2023.286008

Keywords:

thieno[2,3-d]pyrimidine, amides, coupling, docking study, thieno[2,3-d]pyrimidine, amides, coupling, docking study, antimicrobials

Abstract

The aim. The combination in one molecule of pharmacophore fragments of thieno[2,3-d]pyrimidine-4-carboxylic acids with the fragments of 2- or 4-aminopyrimidine by peptide coupling promoted acylation in order to develop the new drug-like molecules with antimicrobial activity.

Materials and methods. The molecular docking studies were performed with the AutoDock Vina та AutoDockTools 1.5.6 programs; TrmD Pseudomonas aeruginosa PDB ID – 5ZHN was used as the protein target. Synthetic methods of peptide coupling were used. 1H and 13C NMR spectra were recorded with a Varian-400 spectrometer at 400 MHz and Bruker Avance DRX 500 device at 500 MHz and 125 MHz in DMSO-d6 as a solvent, using TMS as the internal standard. LC-MS analysis of the compounds was carried out with Agilent 1100 HPLC з with atmospheric pressure chemical ionization (APCI). The studied derivates were tested in vitro for their antibacterial and anti-fungal activities using agar diffusion and serial dilutions resazurin-based microdilution assays (RBMA).

Results and discussion. By the combination of the pharmacophore fragments of thieno[2,3-d]pyrimidine-4-carboxylic acids with the fragments of 2- of 4-aminopyrimidine, the combinatorial library of amides was constructed. For this library of compounds, the potential of antimicrobial activity was revealed using docking studies to the TrmD enzyme isolated from P. aeruginosa. The peptide coupling promoted by 1,1'-carbonyldiimidazole was found to be effective for the synthesis of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acids, and it allowed to combine these pharmacophores in one molecule. The results of antimicrobial activity study revealed the broad spectrum of antimicrobial activity for N-(pyridin-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4-carboxamide (2g), while 5,6-dimethyl-N-(6-methylpyridin-2-yl)thieno[2,3-d]pyrimidine-4-carboxamide (2c) showed the best MIC value against the reference strain of Pseudomonas aeruginosa ATCC 10145. N-(6-Methylpyridin-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4-carboxamide (2h) was also found to be active against Pseudomonas aeruginosa.

Conclusions. An effective method for the synthesis of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acid has been developed. The amides molecular docking method showed their ability to inhibit TrmD enzyme isolated from P. aeruginosa; the further in vitro studies of the compounds showed the rationality of the further studies of the derivatives with 2-amino-6-methylpyridine in amide substituent because this fragment favoured the selectivity against Pseudomonas aeruginosa

Supporting Agency

  • Ministry of Health Care of Ukraine at the expense of the State Budget in 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, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor

Department of Pharmaceutical Chemistry

Hanna Severina, National University of Pharmacy

Doctor of Pharmaceutical Science, Professor

Department of Pharmaceutical Chemistry

Olena Vlasova, National University of Pharmacy

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

Pavlo Shynkarenko, Enamine Ltd.

PhD

Olga Golovchenko, National University of Pharmacy

PhD, Associate Professor

Department of Pharmaceutical Chemistry

Yulian Konechnyi , Danylo Halytsky Lviv National Medical University

PhD

Department of Microbiology

Victoriya Georgiyants, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor, Head of the Department

Department of Pharmaceutical Chemistry

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Synthesis, docking study and antimicrobial activity evaluation of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acid

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Published

2023-10-31

How to Cite

Vlasov, S., Severina, H., Vlasova, O., Borysov, O., Shynkarenko, P., Golovchenko, O., Konechnyi , Y., & Georgiyants, V. (2023). Synthesis, docking study and antimicrobial activity evaluation of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acid. ScienceRise: Pharmaceutical Science, (5(45), 53–62. https://doi.org/10.15587/2519-4852.2023.286008

Issue

No. 5(45) (2023)

Section

Pharmaceutical Science

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Copyright (c) 2023 Sergiy Vlasov, Hanna Severina, Olena Vlasova, Oleksandr Borysov, Pavlo Shynkarenko, Olga Golovchenko, Yulian Konechnyi , Victoriya Georgiyants

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