Surur Abdrrahman S, Bandaru Siva S M, Fischer Christian, Nguyen Van T D, Link Andreas, Bednarski Patrick J, Schulzke Carola
Department of Medicinal and Pharmaceutical Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald 17489, Germany.
Department of Bioinorganic Chemistry, Institute of Biochemistry, University of Greifswald, Greifswald 17489, Germany.
ACS Omega. 2025 Aug 13;10(33):37985-37993. doi: 10.1021/acsomega.5c05115. eCollection 2025 Aug 26.
Fexinidazole, a drug active against trypanosomiasis and leishmaniasis, is a rare example of a nitroaromatic compound approved under the contemporary drug discovery framework. In an earlier study, we showed that the nitro group is absolutely required for antileishmanial activity. The current study employed X-ray crystallography to unveil the structural intricacies of fexinidazole and its principal metabolites, as well as electroanalytical analyses to characterize the reduction properties of the aromatic nitro group. Fexinidazole showcases a predominantly planar geometry with two distinct conformers. While most metrical parameters were conserved between fexinidazole and its metabolites, differences in the methyl ether bridge and -methyl tail indicated distinctive preferences in molecular arrangement: conformer I of fexinidazole closely resembles the sulfone metabolite, while conformer II aligns with the sulfoxide metabolite. On the other hand, electroanalytical analysis of fexinidazole revealed a pH-dependent, two-step nitro group reduction mechanism, involving an initial concerted transfer of an electron and a proton, followed by the uptake of three electrons and three protons to likely form a hydroxylamine species. These findings characterize the molecular architecture and reduction mechanism of fexinidazole, providing valuable insights into its structural features and activation mechanism required for anti-infective activity.
非昔硝唑是一种对锥虫病和利什曼病有效的药物，是在当代药物发现框架下获批的硝基芳香族化合物的罕见例子。在早期研究中，我们表明硝基对抗利什曼原虫活性是绝对必需的。当前研究采用X射线晶体学来揭示非昔硝唑及其主要代谢物的结构复杂性，以及采用电分析方法来表征芳香硝基的还原特性。非昔硝唑呈现出主要为平面的几何结构，有两种不同的构象。虽然非昔硝唑及其代谢物之间的大多数测量参数是保守的，但甲醚桥和甲基尾的差异表明在分子排列上有独特的偏好：非昔硝唑的构象I与砜代谢物非常相似，而构象II与亚砜代谢物一致。另一方面，对非昔硝唑的电分析揭示了一种pH依赖性的两步硝基还原机制，涉及最初电子和质子的协同转移，随后摄取三个电子和三个质子，可能形成羟胺类物质。这些发现表征了非昔硝唑的分子结构和还原机制，为其抗感染活性所需的结构特征和激活机制提供了有价值的见解。
