Stigliani J L, Bernardes-Génisson V
CNRS, Laboratoire de Chimie de Coordination, LCC, UPR 8241, 205, route de Narbonne, BP 44099, 31077 Toulouse, cedex 4, France; Université de Toulouse, Université Paul-Sabatier, UPS, 118, route de Narbonne, 31062 Toulouse, cedex 9, France.
CNRS, Laboratoire de Chimie de Coordination, LCC, UPR 8241, 205, route de Narbonne, BP 44099, 31077 Toulouse, cedex 4, France.
Ann Pharm Fr. 2019 Mar;77(2):126-135. doi: 10.1016/j.pharma.2018.11.004. Epub 2019 Jan 29.
This work aims at getting more insights into the distinct behavior of S-oxide derivatives of thiocarbonyl-containing antitubercular drugs, in order to better understand their mechanism of action and toxicity.
Computational calculation of relative free energy (ΔΔG) of S-oxide tautomers (sulfine R-C [SO]NH2), sulfenic acid (R-C [S-OH]NH) and sulfoxide (R-C [SHO]NH) derived from thioamide and thiourea antitubercular drugs and an update of the literature data with a new point of view about how the structural features of oxidized primary metabolites (S-oxide) can influence the outcome of the reactions and be determinant for the mechanisms of action and of toxicity of these drugs.
The calculated free energy of S-oxide tautomers, derived from thioamide and thiourea-type antitubercular drugs, supported by some experimental results, revealed that S-oxide derivatives could be found under sulfine and sulfenic acid forms depending on their chemical structures. Thiocarbonyl compounds belonging to the thioamide series are firstly oxidized, in the presence of HO, into the corresponding S-oxide derivatives that are more stable under the sulfine tautomeric form. Otherwise, S-oxides of thiourea-type (acyclic and cyclic) compounds tend to adopt the sulfenic acid tautomeric form preferentially. While the intermediate ethionamide-SO under sulfine form can be isolated and in the presence of HO can undergo further oxidation by a mechanism yielding radical species that are toxic for Mycobacterium tuberculosis and human, thioacetazone-SO, found mainly into sulfenic acid form, is unstable and sufficiently reactive in biological conditions to intercept different biochemical pathways and manifests thus its toxicity.
Based on experimental and theoretical data, we propose that S-oxide derivatives of thioamide and thiourea-type antitubercular drugs have preference for distinct tautomeric forms. S-oxide of ethioamide is preferentially under sulfine form whereas S-oxide of thiourea compound as thioacetazone is mainly found under sulfenic acid form. These structural features lead to individual chemical reactivities that might explain the distinct mechanism of action and toxicity observed for the thioamide and thiourea antitubercular drugs.
这项工作旨在更深入地了解含硫代羰基抗结核药物的S - 氧化物衍生物的独特行为，以便更好地理解其作用机制和毒性。
对硫代酰胺和硫脲类抗结核药物的S - 氧化物互变异构体（亚磺酰R - C[SO]NH₂）、亚磺酸（R - C[S - OH]NH）和亚砜（R - C[SHO]NH）的相对自由能（ΔΔG）进行计算，并从新的角度更新文献数据，即氧化初级代谢产物（S - 氧化物）的结构特征如何影响反应结果以及如何决定这些药物的作用机制和毒性。
由硫代酰胺和硫脲类抗结核药物衍生的S - 氧化物互变异构体的计算自由能，在一些实验结果的支持下，表明S - 氧化物衍生物可根据其化学结构以亚磺酰和亚磺酸形式存在。硫代酰胺系列的硫代羰基化合物在HO存在下首先被氧化为相应的S - 氧化物衍生物，这些衍生物在亚磺酰互变异构形式下更稳定。否则，硫脲类（无环和环状）化合物的S - 氧化物倾向于优先采用亚磺酸互变异构形式。虽然亚磺酰形式的中间乙硫异烟胺 - SO可以分离出来，并且在HO存在下可以通过产生对结核分枝杆菌和人类有毒的自由基物种的机制进行进一步氧化，但主要以亚磺酸形式存在的硫代乙酰胺 - SO不稳定，在生物条件下具有足够的反应活性来拦截不同的生化途径，从而表现出其毒性。
基于实验和理论数据，我们提出硫代酰胺和硫脲类抗结核药物的S - 氧化物衍生物对不同的互变异构形式有偏好。乙硫异烟胺的S - 氧化物优先以亚磺酰形式存在，而硫脲化合物如硫代乙酰胺的S - 氧化物主要以亚磺酸形式存在。这些结构特征导致了个体化学反应性，这可能解释了硫代酰胺和硫脲类抗结核药物观察到的不同作用机制和毒性。
