Synthesis and characterization of two asymmetrical 2-cyclohexylsulfenyl-5-alkylsulfenyl[1,3,4]thiadiazoles and study the impact of substituents on the structural features, thermal behavior, and anti-bacterial activity

Regarding the importance of 1,3,4-thiadiazoles due to versatile biological activity and for investigation of the symmetry impact on thermal behavior and antibacterial activity of 2,5-bisalkylsulfenyl[1,3,4]thiadiazole, two new derivatives viz. 2-cyclohexylsulfenyl-5-cyclopentylsulfenyl[1,3,4]thiadiazole and 2-cyclohexylsulfenyl-5-dodecylsulfenyl[1,3,4]thiadiazole, were synthesized through the nucleophilic substitution reaction appropriate alkyl halide with 5-cyclohexyl-3H-[1,3,4]thiadiazole-2-thione in ethanol under reflux conditions. The chemical structure of the products was elucidated by the physical and spectroscopic techniques. After tedious work, the suitable snow-like crystals of 2-cyclohexylsulfenyl-5-dodecylsulfenyl[1,3,4]thiadiazole for single-crystal X-ray diffraction analysis could be isolated from a mixed solvent, namely ethanol and water in volume ratio of 9:1. Then, the influence of symmetry and cyclic or non-cyclic aliphatic substituents on the important structure parameters of the 2,5-bisalkylsulfenyl[1,3,4]thiadiazole derivatives were negligible, however, those structure characteristics were different for 5–cyclohexylsulfenyl–3H–[1,3,4]thiadiazole–2–thione, due to its thione structure. TGA/DTA study demonstrated the effect of the symmetry and van der Waals interaction on thermal stability, and the robust influence of the pseudo hydrogen bonding NH with C = S on the melting and crystallization phase transitions was revealed by DSC analysis. The pharmacokinetics, drug-likeness, medicinal chemistry friendliness, and toxicology of three derivatives of bis-alkylsulfenyl[1,3,4]thiadiazole were evaluated by two prediction tools of SwissADME and T.E.S.T tools predicted good pharmacokinetics, drug-likeness, and anti-toxicant properties in developmental toxicity for the bis-alkylsulfenyl[1,3,4]thiadiazoles and 5–cyclohexylsulfenyl–3H–[1,3,4]thiadiazole–2–thione. Finally, the in vitro antibacterial activity of two new 2-cyclohexylsulfenyl-5-cyclopentylsulfenyl[1,3,4]thiadiazole and 2-cyclohexylsulfenyl-5-dodecylsulfenyl[1,3,4]thiadiazole against S. aureus and E. coli, confirmed them as promising anti-bacterial agent. All obtained results proved that the physicochemical, thermal, pharmacokinetic, and biological properties of 2,5-bisalkylsulfenyl[1,3,4]thiadiazoles can be tuned by selecting appropriate substituents.

鉴于1,3,4-噻二唑（1,3,4-thiadiazoles）具备多样的生物活性，且为探究对称性对2,5-双烷硫基[1,3,4]噻二唑（2,5-bisalkylsulfenyl[1,3,4]thiadiazole）的热行为与抗菌活性的影响，本研究通过亲核取代反应，以乙醇为溶剂、在回流条件下，使合适的卤代烷与5-环己基-3H-[1,3,4]噻二唑-2-硫酮（5-cyclohexyl-3H-[1,3,4]thiadiazole-2-thione）反应，合成了两种新型衍生物，即2-环己基硫基-5-环戊基硫基[1,3,4]噻二唑（2-cyclohexylsulfenyl-5-cyclopentylsulfenyl[1,3,4]thiadiazole）与2-环己基硫基-5-十二烷基硫基[1,3,4]噻二唑（2-cyclohexylsulfenyl-5-dodecylsulfenyl[1,3,4]thiadiazole）。采用物理与光谱技术对产物的化学结构进行了表征。经繁琐的后处理操作后，可从体积比为9:1的乙醇-水混合溶剂中分离得到适用于单晶X射线衍射（single-crystal X-ray diffraction）分析的2-环己基硫基-5-十二烷基硫基[1,3,4]噻二唑雪状单晶。研究发现，对称性与环状、非环状脂肪族取代基对2,5-双烷硫基[1,3,4]噻二唑衍生物的关键结构参数影响可忽略不计；但对于5-环己基硫基-3H-[1,3,4]噻二唑-2-硫酮而言，由于其硫酮结构，其结构特征存在显著差异。热重/差热（TGA/DTA）分析表明，对称性与范德华相互作用（van der Waals interaction）对热稳定性存在调控作用；而差示扫描量热法（DSC）分析则揭示了NH与C=S之间的准氢键对熔融与结晶相变过程的显著影响。通过SwissADME与T.E.S.T两款预测工具，对三种双烷硫基[1,3,4]噻二唑衍生物的药代动力学（pharmacokinetics）、类药性（drug-likeness）、药物化学友好性（medicinal chemistry friendliness）及毒理学（toxicology）进行了评估。结果显示，双烷硫基[1,3,4]噻二唑与5-环己基硫基-3H-[1,3,4]噻二唑-2-硫酮具备良好的药代动力学特性与类药性，且在发育毒性方面表现出抗毒活性。针对金黄色葡萄球菌（S. aureus）与大肠杆菌（E. coli）的体外抗菌活性（in vitro antibacterial activity）实验证实，两种新型衍生物2-环己基硫基-5-环戊基硫基[1,3,4]噻二唑与2-环己基硫基-5-十二烷基硫基[1,3,4]噻二唑均为极具潜力的抗菌剂。本研究所有结果均证明，通过选择合适的取代基，可精准调控2,5-双烷硫基[1,3,4]噻二唑的物理化学、热学、药代动力学及生物学性质。