Medicinal chemistry (Shariqah (United Arab Emirates)) · 2026
Indole-2-carboxylic Acid Hydrazones and Hydroxamic Acid Derivatives: Synthesis and Evaluation of Biological Properties.
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Tiuleanu Pavel, Ivanov Ivan V, Andreeva Irina P, Grigorenko Vitaly G, Dezhenkova Lybov G, Egorov Alexey M, Shchekotikhin Andrey E
Аннотация
INTRODUCTION: The indole nucleus is considered a privileged pharmacophore in medicinal chemistry. Indole-2-carboxylic acid derivatives are valued for their antiproliferative and antibacterial properties, including the potential to overcome drug resistance. This study aimed to synthesize novel salicylidene hydrazones of indole-2-carboxylic acid and evaluate their potential as metallo-β-lactamase (NDM-1) inhibitors and antiproliferative agents alongside previously reported indole-2-carboxylic acid derivatives.
METHODS: A novel series of salicylidene hydrazones of indole-2-carboxylic acid was synthesized with potential as metallo-β-lactamase inhibitors in mind. All compounds were evaluated for their inhibitory activity against NDM-1 and tested for antiproliferative potency against human chronic myelogenous leukemia K-562 cells and the multidrug-resistant (MDR) subline K- 562/4. Doxorubicin and previously reported indole derivatives (1, 5, 6) were used as reference compounds.
RESULTS: Unlike the parent acid 1, the novel derivatives showed weak NDM-1 inhibition (IC50 > 50 μM). In contrast, salicylidene hydrazones 4a-g demonstrated strong antiproliferative activity (IC50 = 0.15-0.80 μM). This effect was particularly pronounced against the MDR subline K- 562/4. Notably, the IC50 values for several derivatives were up to 50-fold lower than that of doxorubicin against resistant cells. Hydrazide 3, hydrazones 4h and 4i, thiosemicarbazide 5, and hydroxamic acids 6a-c showed moderate antiproliferative activity (IC50 = 2.4-13.3 μM).
DISCUSSION: The weak NDM-1 inhibition confirms that a free 2-carboxyl group is critical for binding within the enzyme's active site. However, converting this scaffold into salicylidene hydrazones significantly enhances antiproliferative potency. It also effectively enables the circumvention of P-glycoprotein (P-gp) mediated efflux in MDR leukemia cells.
CONCLUSION: Indole-2-carboxylic acid salicylidene hydrazones emerged as promising scaffolds for developing new anticancer agents. They exhibit potent activity against leukemia cells, particularly against the P-gp-overexpressing MDR subline K-562/4.
METHODS: A novel series of salicylidene hydrazones of indole-2-carboxylic acid was synthesized with potential as metallo-β-lactamase inhibitors in mind. All compounds were evaluated for their inhibitory activity against NDM-1 and tested for antiproliferative potency against human chronic myelogenous leukemia K-562 cells and the multidrug-resistant (MDR) subline K- 562/4. Doxorubicin and previously reported indole derivatives (1, 5, 6) were used as reference compounds.
RESULTS: Unlike the parent acid 1, the novel derivatives showed weak NDM-1 inhibition (IC50 > 50 μM). In contrast, salicylidene hydrazones 4a-g demonstrated strong antiproliferative activity (IC50 = 0.15-0.80 μM). This effect was particularly pronounced against the MDR subline K- 562/4. Notably, the IC50 values for several derivatives were up to 50-fold lower than that of doxorubicin against resistant cells. Hydrazide 3, hydrazones 4h and 4i, thiosemicarbazide 5, and hydroxamic acids 6a-c showed moderate antiproliferative activity (IC50 = 2.4-13.3 μM).
DISCUSSION: The weak NDM-1 inhibition confirms that a free 2-carboxyl group is critical for binding within the enzyme's active site. However, converting this scaffold into salicylidene hydrazones significantly enhances antiproliferative potency. It also effectively enables the circumvention of P-glycoprotein (P-gp) mediated efflux in MDR leukemia cells.
CONCLUSION: Indole-2-carboxylic acid salicylidene hydrazones emerged as promising scaffolds for developing new anticancer agents. They exhibit potent activity against leukemia cells, particularly against the P-gp-overexpressing MDR subline K-562/4.