Novel 3-thio-1,2,4- and 1,2,3-triazole derivatives as allosteric glutaminase inhibitors

Cancer cells, including those in triple-negative breast cancer (TNBC), often rely on glutamine metabolism. The enzyme glutaminase (GLS) converts glutamine to glutamate, thereby fueling the TCA cycle and affecting cell proliferation and differentiation. This metabolic dependency makes GLS a promising therapeutic target in cancer therapy, with inhibitors currently in clinical trials. Considering the key role of triazoles in medicinal chemistry and the need for the development of new drugs against cancer, we herein report the design and synthesis of a new series of 3-thio-1,2,4-triazoles from a variety of acyl hydrazines and alkyl isothiocyanates in good yields, along with 1,2,3-triazole derivatives obtained by click chemistry. A structure-activity relationship (SAR) study was performed to evaluate their potential to inhibit GLS through an enzyme inhibition assay. Among the library synthesized, compound 10k exhibited the most potent activity, exhibiting an IC50 of 9 µM. To shed light on the possible mode of interaction with GLS, molecular docking was performed, and the results point to a new allosteric binding site for compound 10k.