Biological evaluation and molecular modelling study of thiosemicarbazide derivatives as bacterial type IIA topoisomerases inhibitors

Abstract

In the present article, we describe the inhibitory potency of nine thiosemicarbazide derivatives against bacterial type IIA topoisomerases, their antibacterial profile and molecular modelling evaluation. We found that one of the tested compounds, compound 7, significantly inhibits activity of Staphylococcus aureus DNA gyrase with an IC 50 below 15 mM. Besides, this compound displays antibacterial activity on reference Staphylococuss spp. and Enterococcus faecalis strains as well as clinical S. aureus isolates at non-cytotoxic concentrations in mammalian cells with MIC values ranging from 16 to 32 mg/mL thereby indicating, in some cases, equipotent or even more effective action than standard drugs such as vancomycin, ampicillin and nitrofurantoin. The computational studies showed that both molecular geometry and the electron density distribution have a great impact on antibacterial activity of thiosemicarbazide derivatives.

Lipophilicity Studies on Thiosemicarbazide Derivatives

“…Therefore, the second part of our studies was dedicated to determining the role of lipophilicity on the inhibitory action of 1-hetaroyl-4-substituted-thiosemicarbazides against bacterial type IIA topoisomerases. Lead compounds from this series were reported to be potent and non-toxic inhibitors [ 17 , 18 , 19 ] ( Table 5 ) and can be considered as a starting point for the development of improved antibacterial agents. Although a correlation of their inhibitory potency with hydrophobic/hydrophilic balance was suggested to exist, no such trend could be deduced from the comparison of their calculated logP values.…”

“…Recently, as part of our efforts to discover new molecules that might be used to combat clinically significant infections, for the first time we have documented inhibitory properties of 1,4-disubstituted thiosemicarbazides towards bacterial DNA gyrase and topoisomerase IV [ 17 , 18 , 19 ]. Unfortunately, results of the bacterial type IIA topoisomerases inhibition study did not parallel the antibacterial activities.…”

Synthesis and Anthelmintic Activity of New Thiosemicarbazide Derivatives—A Preliminary Study

“…Thiosemicarbazides are very similar to thiosemicarbazones. A thiosemicarbazide skeleton is part of the structure of many compounds with interesting biological activities, including anticancer [ 10 , 11 , 12 , 13 ], antibacterial [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ], antifungal [ 19 ], and analgesic [ 20 ].…”

Docking and QSAR of Aminothioureas at the SARS-CoV-2 S-Protein–Human ACE2 Receptor Interface

“…While repurposing of compounds currently in medical use is necessary for a quick response to this public health threat, in the long run, drugs specific to this particular virus will be needed. With this aim in mind, we used the SARS-CoV-2 S-protein–ACE2 receptor complex model and its components to evaluate the binding properties of thiosemicarbazides, thiadiazoles, and triazoles that we previously studied for their anti- Toxoplasma gondi [ 22 , 23 , 24 , 25 ], antiviral [ 26 ], antibacterial [ 27 , 28 , 29 , 30 , 31 , 32 ], anticancer [ 17 , 33 , 34 , 35 ], anticonvulsant [ 36 , 37 , 38 ], analgesic [ 39 , 40 ] activities.…”