Synthesis and antimicrobial activity of new 2-piperazin-1-yl-N-1,3-thiazol-2-ylacetamides of cyclopenta[c]pyridines and pyrano[3,4-c]pyridines

In this study, we report the synthesis and antimicrobial activity of some new disubstituted piperazines. Thus, 3-chlorocyclopenta[c]pyridines and 6-chloropyrano[3,4-c]pyridine1under mild reaction conditions with piperazine gave the 3(6)-piperazine-substituted cyclopenta[c]pyridines and pyrano[3,4-c]pyridine2. Furthermore, the latter, by alkylation with 2-chloro-N-1,3-thiazol-2-ylacetamide, led to the formation of the target compounds. The evaluation of the antibacterial activity revealed that3kwas the most potent compound. The most sensitive bacterium was found to beListeria monocytogenes, whereasStaphylococcus aureuswas the most resistant one. Three compounds,3d,3g, and3k, were tested also against the following resistant strains: methicillin-resistantS. aureus(MRSA),Escherichia coli, andPseudomonas aeruginosa. All three compounds appeared to be more potent than ampicillin against MRSA. Moreover, compound3dshowed a better activity than the reference drug ampicillin againstP. aeruginosa, whereas3gwas more efficient againstE. coli. The best antifungal activity was observed again for compound3k. The most resistant fungi appeared to beAspergillus fumigatus, whereasTrichoderma virideseemed the most sensitive one toward the compounds tested. Molecular docking studies onE. coliMurB, as well as onCandida albicansCYP51 and dihydrofolate reductase, were used for the prediction of the mechanisms of the antibacterial and antifungal activities, confirming the experimental results.

Automated summary

This study reported the synthesis and antimicrobial activity of new disubstituted piperazines. Compound 3k showed the highest potency against bacteria, with Listeria monocytogenes being the most sensitive and Staphylococcus aureus being the most resistant. Molecular docking studies confirmed the experimental results on the mechanisms of antibacterial and antifungal activities.