Synthesis, characterization, and impact of carbon spacer on 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

Regarding the importance of 1,3,4-thiadiazoles due to their 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 was synthesized and characterized using various spectroscopic techniques. The pharmacokinetics/ADMET properties and toxicity of 1,3,4-thiadiazole (TD) derivatives were predicted using bioinformatic tools, i.e., SwissADME and ProToX-III. The in vitro antibacterial activity of 1,3,4-thiadiazole derivatives was studied. Finally, the ability of these derivatives to interact with the target proteins of 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 envelop 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 in class VI and IV toxicity, respectively. Given MIC value of 2-64 μg mL−1 for all derivatives, their high antibacterial activity was demonstrated. The antibacterial activity of C5C6TD and C6C6TD was 2 μg mL−1 for E. coli and 8 μg mL−1 for 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.