Ultrasound-Assisted Synthesis and In Silico Modeling of Methanesulfonyl-Piperazine-Based Dithiocarbamates as Potential Anticancer, Thrombolytic, and Hemolytic Structural Motifs.

Piperazine-based dithiocarbamates serve as important scaffolds for numerous pharmacologically active drugs. The current study investigates the design and synthesis of a series of dithiocarbamates with a piperazine unit as well as their biological activities. Under ultrasound conditions, the corresponding piperazine-1-carbodithioates were synthesized from monosubstituted piperazine and -phenylacetamides in the presence of sodium acetate and carbon disulfide in methanol. The structures of the newly synthesized piperazines were confirmed, and their anti-lung carcinoma effects were evaluated. A cytotoxic assay was performed to assess the hemolytic and thrombolytic potential of the synthesized piperazines . The types of substituents on the aryl ring were found to affect the anticancer activity of piperazines . Piperazines containing 2-chlorophenyl (; cell viability = 25.11 ± 2.49) and 2,4-dimethylphenyl (; cell viability = 25.31 ± 3.62) moieties demonstrated the most potent antiproliferative activity. On the other hand, piperazines containing 3,4-dichlorophenyl (; 0.1%) and 3,4-dimethylphenyl (; 0.1%) rings demonstrated the least cytotoxicity. The piperazine with the 2,5-dimethoxyphenyl moiety (; 60.2%) showed the best thrombolytic effect. To determine the mode of binding, in silico modeling of the most potent piperazine (i.e., ) was performed, and the results were in accordance with those of antiproliferation. It exhibits a similar binding affinity to PQ10 and an efficient conformational alignment with the lipophilic site of PDE10A conserved for PQ10A.