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This study aimed to evaluate the cytotoxic effects of nine synthetic compounds incorporating annulated benzimidazole and nitrothiazole scaffolds in two glioblastoma cell lines (A172 and U87-MG) under both normoxic and hypoxic conditions. Three compounds (BZM-7, BZM-9, and CNZ-3) demonstrated potent anticancer activity, with CNZ-3 exhibiting the highest efficacy, particularly in hypoxia. The study further investigated the effects of these compounds on the expression of the G6PD gene, as well as post-translational regulatory genes SIRT2 and KAT9, and the angiogenesis-related VEGF gene. Transcriptional analyses showed that the nitrothiazole-derived compound CNZ-3 significantly downregulated G6PD, SIRT2, KAT9 and VEGF expression under hypoxic conditions, suggesting selective interference with hypoxia-adaptative pathways. In contrast, BZM-7 and BZM-9 showed distinct expression patterns, indicating diverse mechanisms of action despite structural similarity. In addition, BZM-7, BZM-9, and CNZ-3 were identified as potent inhibitors of recombinant G6PD, demonstrating both enzymatic inhibition and structural alterations, suggesting that G6PD could be a relevant therapeutic target for these compounds. Furthermore, molecular docking analysis revealed favorable binding interactions between the compounds and key amino acids of the G6PD, reinforcing their potential as a direct enzyme inhibitors. These findings highlight the pivotal role of G6PD in gliomas under hypoxic conditions and support its inhibition as a promising therapeutic strategy.<\/jats:p>","DOI":"10.3390\/ijms26189092","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T12:54:26Z","timestamp":1758200066000},"page":"9092","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting G6PD with Benzimidazole and Thiazole Derivatives Suppresses SIRT 2 and VEGF Expression and Induces Cytotoxicity in Glioma Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4651-7892","authenticated-orcid":false,"given":"Montserrat","family":"V\u00e1zquez-Bautista","sequence":"first","affiliation":[{"name":"Laboratorio de Bioqu\u00edmica Gen\u00e9tica, Instituto Nacional de Pediatr\u00eda, Secretar\u00eda de Salud, Mexico City 04530, Mexico"},{"name":"Programa de Posgrado en Biomedicina y 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