Synthesis, Antibacterial Properties and Molecular Docking Studies of Nitrogen Substituted 9-(((4X-But-2-ynyloxy)methyl)-1,2,3-triazolyl)–Cinchona Alkaloid Conjugates

Mukusheva G.K. Toigambekova N.N. Savelyev V.A. Khlebnikov A.I. Burova L.G. Afanaseva S.D. Nurkenov O.A. Kishkentayeva A.S. Olzhabayeva A.S. Gatilov Y.V. Seidakhmetova R.B. Evstropov A.N. Shults E.E.
November 2025 Multidisciplinary Digital Publishing Institute (MDPI)

Molecules
2025 #30 Issue 22

The year 2024 marked the 80th anniversary of Woodward’s total synthesis of quinine. Quinine is a natural alkaloid from the bark of the cinchona tree that has been used for years as an antimalarial drug. The antibacterial effect of quinine salts has also been regarded. With this in mind, a series of original 9-deoxycinchone alkaloid derivatives bearing a dialkylamino- or heterocyclic moiety at the 4 position of the 9-(((4-X-but-2-ynyloxy)methyl)-1,2,3-triazolyl)-substituent was synthesized. The copper-catalyzed three-component A³-coupling reaction of 9-(((4-prop-2-ynyloxy)methyl)-1,2,3-triazolyl)- substituted cinchona alkaloid derivatives with secondary amines and formaldehyde was the main route of synthesis. The present study attempted to examine the antibacterial properties of 9-substituted 9-desoxyquinine-derived compounds and their antibacterial activity against pathogenic bacterial strains, e.g., Staphylococcus aureus, Bacillus subtillis, Bacillus cereus, and Escherichia coli. The difference in the antibacterial activity profile of diastereoisomeric 9-(((4-X-but-2-ynyloxy)methyl)-1,2,3-triazolyl)-substituted derivatives of cinchona alkaloids indicated the importance of the nature of nitrogen substituents in the molecules. In a concentration-dependent pattern, (9R)- and (9S)- (((4-asocan-1yl)-but-2-ynyl-oxy)methyl)-1,2,3-triazolyl)-substituted compounds demonstrated considerable biofilm-inhibitory efficacy against the S. aureus bacterial strain. A detailed study of the molecular interactions with the targeted protein MurB was performed using docking simulations, and the obtained results are quite promising.

A³-coupling reactions , antibacterial activity , bacterial biofilms , cinchona alkaloids , molecular docking study , quinine , triazoles

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Chemistry Faculty, Karaganda National Research University Buketov, Karaganda, 100024, Kazakhstan
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
Kizhner Research Center, Tomsk Polytechnic University, Tomsk, 634050, Russian Federation
Department of Microbiology, Immunology and Virology, Novosibirsk State Medical University, Krasny Prospect 52, Novosibirsk, 630091, Russian Federation
Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan, Karaganda, 100008, Kazakhstan
School of Pharmacy, Karaganda Medical University, Karaganda, 100012, Kazakhstan
Department of Clinical Pharmacology and Evidence-Based Medicine, Karaganda Medical University, Karaganda, 100012, Kazakhstan

Chemistry Faculty
Vorozhtsov Novosibirsk Institute of Organic Chemistry
Kizhner Research Center
Department of Microbiology
Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan
School of Pharmacy
Department of Clinical Pharmacology and Evidence-Based Medicine

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