Design, Synthesis, Antibacterial Evaluations and In Silico Studies of Novel Thiosemicarbazides and 1,3,4-Thiadiazoles

Abstract

The emergence of drug-resistant bacterial strains continues to be one of the major challenges of medicine. For this reason, the importance of searching for novel structures of antibacterial drugs chemically different from the currently known antibiotics is still of great importance. In this study, we synthesized the thiosemicarbazide and 1,3,4-thiadiazole derivatives and tested them for antibacterial activity. In in vitro tests, we examined the activity of the synthesized substances against Gram-positive and Gram-negative bacteria strains. While all 1,3,4-thiadiazoles tested lacked significant activity, the antimicrobial response of the thiosemicarbazides was moderate and it was also dependent on the type and position of the substituent on the phenyl ring. The highest activity towards all Gram-positive bacteria strains was shown by all three linear compounds containing the trifluoromethylphenyl group in the structure. The MIC (minimum inhibitory concentration) values were in the range of 3.9–250 µg/mL. Additionally, we try to explain the mechanism of the antibacterial activity of the tested compounds using the molecular docking to DNA gyrase and topoisomerase IV, following previous reports on the molecular basis of the activity of thiosemicarbazides. Docking simulations allow the purposing dual mechanism of the antibacterial activity of the synthesized compounds through inhibition of topoisomerase IV DNA gyrase with the moderate prevalence of the topoisomerase pathway.

Drug Delivery Systems Based on Pluronic Micelles with Antimicrobial Activity

“…Moreover, the lack of the antibacterial activity against P. aeruginosa and P. gingivalis demonstrate that our system is highly selective in killing different strains of bacteria, and this can be considered an important advantage. Concerning the molecular mechanism of the antibacterial activity of these types of compounds, it is still under debate in the literature, but it seems that the inhibitory action towards bacterial topoisomerases could be the main explanation [ 37 , 38 ]. Undoubtedly, more in-depth research in this area is urgently needed in order to establish the exact mechanism of action of these compounds.…”

Synthesis, Molecular Docking Study, and Cytotoxicity Evaluation of Some Novel 1,3,4-Thiadiazole as Well as 1,3-Thiazole Derivatives Bearing a Pyridine Moiety

“…Among those, 1,3,4-thiadiazoles gained substantial interest due to their widespread biological activity, including antimicrobial, anti-inflammatory, antithrombotic, antihypertensive, antituberculosis, anesthetic, anticonvulsant and antiulcer activities [ 11 , 12 , 13 , 14 , 15 , 16 ]. Furthermore, different researchers also particularly report 1, 3, 4-thiadiazole derivatives for their excellent anticancer activity, which are confirmed by desirable IG 50 and IC 50 values in inhibitory effect, such as Filanesib and compounds I–III ( Figure 1 ) [ 16 , 17 , 18 , 19 , 20 ].…”

Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII

“…Extensive original contributions either on coumarin- and thiosemicarbazide-containing structures are reported every year within the field of Medicinal Chemistry and other disciplines not necessarily related to each other [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. The unique features of such moieties (i.e., electronic/chemical) along with the straightforward synthetic access are the main reason for them being considered privileged scaffolds endowed with versatile biomedical applications [ 1 , 4 , 7 , 8 , 9 ]. In this context, researchers have largely contributed to the field by demonstrating that the coumarin ring effectively inhibits the α-carbonic anhydrase (CA; EC 4.2.1.1) enzymes and acts as a prodrug by making use of the lactone ring [ 10 ].…”

“…Such a discovery is of particular value since large amounts of coumarin compounds are derived from natural sources (i.e., in majority from plants) and thus de facto legitimized direct retrieval of CA inhibitors (i.e., CAIs) from the “natural chemical repository”. A variety of biological activities have been attributed to the thiosemicarbazide moiety (i.e., anti-cancer, anti-microbial, anti-viral, antioxidant properties), however a clear definition of its role in biology still remains blurred, mainly regarding the multiple and overlapping biological events triggered [ 7 , 8 , 9 ]. In this context we sought to investigate the inhibitory effects of coumarin-based CAIs functionalized with variegate thiosemicarbazide-containing tails on the physio/pathologically relevant hCA isoforms I, II, IX and XII.…”

“…Extensive original contributions either on coumarin-and thiosemicarbazide-containing structures are reported every year within the field of Medicinal Chemistry and other disciplines not necessarily related to each other [1][2][3][4][5][6][7][8][9]. The unique features of such moieties (i.e., electronic/chemical) along with the straightforward synthetic access are the main reason for them being considered privileged scaffolds endowed with versatile biomedical applications [1,4,[7][8][9].…”