Indole-2-Carboxamide Derivatives: Synthesis and Estimation of Their Potential as Metallo-Beta-Lactamase Inhibitors

Tiuleanu, Р.; Ivanov, I.V.; Solov’eva, S.E.; Andreeva, I.P.; Grigorenko, V.G.; Egorov, A.M.; Shchekotikhin, A.E.

Авторы: Tiuleanu Р., Ivanov I.V., Solov’eva S.E., Andreeva I.P., Grigorenko V.G., Egorov A.M., Shchekotikhin A.E.
Журнал: Russian Journal of Organic Chemistry
Том: 61
Номер: 6
Год издания: 2025
Издательство: Maik Nauka/Interperiodica Publishing
Местоположение издательства: Russian Federation
Первая страница: 1134
Последняя страница: 1140
DOI: 10.1134/s1070428025602511
Аннотация: Bacterial resistance to β-lactam antibiotics is one of the key challenges in global healthcare. A major mechanism underlying this resistance is the production of β-lactamases by pathogens. These enzymes are classified into four groups (A–D), with class B metallo-β-lactamases, particularly the NDM family, posing the highest threat. These zinc-dependent enzymes are capable of inactivating nearly all β-lactam antibiotics, and to date, there are no clinically approved inhibitors for this class. Previous studies have shown that certain derivatives of indole-2-carboxylic acid, hydroxamic acids, and glycine-based compounds can inhibit NDM-1 by interacting with Zn2+ ions and amino acid residues within the enzyme’s active site. However, the antibacterial potential of indole-2-carboxamide derivatives of the aforementioned compounds has not yet been explored as inhibitors of metallo-β-lactamases. In the search for new candidates to develop specific metallo-β-lactamase inhibitors, a known indole-2-carboxylic acid-based NDM-1 inhibitor was modified to prepared previously undescribed analogues—indole-2-carboxamides bearing fragments derived from hydroxamic acid, glycine, and iminodiacetic acid. To accomplish this, a method commonly used in peptide synthesis was adapted, employing the condensing agent PyBOP. The resulting compounds demonstrated the ability to inhibit NDM-1 in the micromolar concentration range (IC50 = 20–60 µM), highlighting the significant role of the substituent at position 2 in binding to the enzyme’s active site. It was shown that modifying the carboxyl group at position 2 of the indole core with functional fragments possessing intrinsic inhibitory activity leads to a reduction in the activity of the parent indole-2-carboxylic acid derivative.
Добавил в систему: Григоренко Виталий Георгиевич

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Indole-2-Carboxamide Derivatives: Synthesis and Estimation of Their Potential as Metallo-Beta-Lactamase Inhibitorsстатья

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