Synthesis, characterization, and impact of a carbon spacer on the geometry and antibacterial activity of a new series of 1,n-bis(5-cycloalkylsulfenyl-1,3,4-thiadiazole-2-sulfenyl) alkanes (n = 4 and 6)

Abstract

Due to the importance of 1,3,4-thiadiazoles with versatile biological activity and for the investigation of the carbon spacer impact on their toxicity and antibacterial activity, a new series of bis(cycloalkylsulfenyl)-1,3,4-thiadiazole derivatives were synthesized and characterized using various spectroscopic techniques. The pharmacokinetics/ADMET properties and toxicity of the 1,3,4-thiadiazole (TD) derivatives were predicted using bioinformatics tools, i.e., SwissADME and ProTox-III. The in vitro antibacterial activity of the 1,3,4-thiadiazole derivatives was studied. Finally, the ability of these derivatives to interact with the target proteins 7MYM and 1T2P was predicted using SwissDock. The crystal data revealed that the two TD rings and six carbon atoms of the spacer were coplanar, and the cyclopentyl rings adopted a slightly twisted-envelope conformation above and below this plane to minimize eclipsed hydrogen atoms, balancing angle and torsional strains. Derivatives with six and four carbon atoms in the spacer were predicted to belong to toxicity class VI and IV, respectively. Given MIC values of 2–64 μg mL⁻¹ for all derivatives, a high antibacterial activity was demonstrated. The antibacterial activity of C5C6TD and C6C6TD was notable, with MIC values of 2 μg mL⁻¹ against E. coli and 8 μg mL⁻¹ against S. aureus. Molecular docking revealed good binding energies and various interactions within the target pocket. These results indicate that the new series of bis(5-cycloalkylsulfenyl-1,3,4-thiadiazole-2-sulfenyl) derivatives is a promising candidate for investigation in other pharmaceutical areas.