Ortiz-Pérez Eyra, Moreno-Rodríguez Adriana, Delgado-Maldonado Timoteo, Ortega-Balleza Jessica L, González-González Alonzo, Paz-González Alma D, Vázquez Karina, Avalos-Navarro Guadalupe, Giovannuzzi Simone, Supuran Claudiu T, Rivera Gildardo
Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Mexico.
Laboratorio de Estudios Epidemiológicos, Clínicos, Diseños Experimentales e Investigación, Facultad de Ciencias Químicas, Universidad Autónoma "Benito Juárez" de Oaxaca, Avenida Universidad S/N, Ex Hacienda Cinco Señores, Oaxaca 68120, Mexico.
Pharmaceuticals (Basel). 2025 May 1;18(5):669. doi: 10.3390/ph18050669.
α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in , the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme's active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with K = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease.
α-碳酸酐酶（α-TcCA）已成为美洲锥虫病病原体克氏锥虫中有前景的药物靶点。磺胺类药物是已知的碳酸酐酶抑制剂，可与酶活性位点上的锌离子结合。本研究提出重新定位基于磺胺类的药物以鉴定新的杀锥虫剂。对靶向α-TcCA的美国食品药品监督管理局（FDA）批准的药物进行了基于配体的虚拟筛选和分子对接分析。这些化合物在体外和体内针对A1和NINOA菌株进行了评估，随后进行了酶活性测定。选择了四种磺酰脲类药物：格列美脲（Glim）、醋磺己脲（Ace）、格列齐特（Glic）和甲苯磺丁脲（Tol）。在无鞭毛体和锥鞭毛体阶段，Ace和Tol对NINOA菌株的半数最大抑制浓度（IC）值与参考药物相似或更好，而Glic和Glim对A1菌株（无鞭毛体和无鞭毛体）具有最高活性。值得注意的是，Ace对NINOA的所有阶段都具有最高的杀锥虫活性，无鞭毛体、锥鞭毛体和无鞭毛体的IC值分别为6.5、46.5和46 μM。此外，Ace以K = 5.6 μM抑制α-TcCA，表明其杀锥虫作用与酶抑制有关。本研究支持将FDA批准的基于磺胺类的降血糖药物重新定位为杀锥虫化合物。未来的研究应集中在结构修饰以提高选择性上。整合对接、寄生虫学和酶学数据对于优化美洲锥虫病候选药物至关重要。
