Synthesis and structure–activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents

Stolić, Ivana; Paljetak, Hana Čipčić; Perić, Mihaela; Matijašić, Mario; Stepanić, Višnja; Verbanac, Donatella; Bajić, Miroslav

doi:10.1016/j.ejmech.2014.11.003

Cited by 26 publications

(16 citation statements)

References 56 publications

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“…As MB17 was a more efficient anti-T. cruzi agent than MB19 and MB38, we investigated its mechanism of action in more detail. Remarkably, in a previous study, MB17, which was the compound with the lowest IC 50 , also showed promising antibacterial activity against Grampositive and Gram-negative bacterial strains compared to the activities of other compounds, including MB19 and MB38 (29). In addition to their antiparasitic effects, these compounds, due to their fluorescence properties, could also be considered promising probes for trypanosome-specific staining (30).…”

Section: Discussionmentioning

confidence: 77%

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Girard

Crispim

Stolić

et al. 2016

Antimicrob Agents Chemother

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dTrypanosoma cruzi is the etiological agent of Chagas disease, affecting approximately 10 million people in the Americas and with some 40 million people at risk. The objective of this study was to evaluate the anti-T. cruzi activity of three new diamidines that have a 3,4-ethylenedioxy extension of the thiophene core, designated MB17, MB19, and MB38. All three diamidines exhibited dose-dependent inhibition of epimastigote replication. The mechanisms of action of these diamidines were investigated. Unlike MB17 and MB19, MB38 exhibited a significant increase in the number of annexin-propidium iodide double-labeled cells compared to levels in control parasites. As MB17 had shown a lower 50% inhibitory concentration (IC 50 ) against epimastigote growth, the mechanism of action of this drug was studied in more detail. MB17 triggered a decrease in the intracellular ATP levels. As a consequence, MB17 affected the genomic DNA and kinetoplast DNA (kDNA) and impaired the parasite cell cycle. Moreover, MB17 caused DNA fragmentation, with a more severe effect on kDNA than on nuclear DNA, resulting in dyskinetoplastic cells. MB17 was tested for toxicity and effectiveness for the treatment of infected CHO-K 1 cells, exhibiting a 50% cytotoxic concentration (CC 50 ) of 13.47 ؎ 0.37 M and an IC 50 of 0.14 ؎ 0.12 M against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 M. In conclusion, despite belonging to the same family, these diamidines have different efficiencies. To summarize, MB17 was the most potent of these diamidines against epimastigotes, producing DNA damage preferentially in kDNA, impairing the parasite cell cycle, and decreasing the infection index and trypomastigote release from infected mammalian host cells, with a high selectivity index (SI) (<90). These data suggest that MB17 could be an interesting lead compound against T. cruzi. A merican trypanosomiasis, or Chagas disease, affects approximately 10 million people, with 40 million people at risk of acquiring the infection. Chagas disease is endemic to South and Central America and the southern states of the United States. Currently, it is also spreading in Europe and the rest of North America due to the immigration of infected people, as well as through transmission of the disease by transfusions, transplants, and congenital mechanisms (1, 2). The disease is caused by the protozoan Trypanosoma cruzi, which shares some distinctive features with other trypanosomes, such as the presence of a flagellum and of a kinetoplast, a complex structure bearing the mitochondrial genome. In this case, the mitochondrial genomic DNA is referred to as kinetoplast DNA, or kDNA. It consists of a great number of relaxed circular DNA molecules interlocked with each other to form a catenated DNA network (3). T. cruzi has a complex life cycle, which occurs within invertebrate and vertebrate hosts (4-6). Chagas disease presents two clinical phases, the acute phase, which appears shortly after infection and is characterized by an evident parasitemia and ...

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Section: Discussionmentioning

confidence: 77%

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Girard

Crispim

Stolić

et al. 2016

Antimicrob Agents Chemother

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“…) showed excellent antibacterial activity against S. aureus , S. pneumoniae , S. pyogenes , Moraxella catarrhalis , E. coli , and Haemophilus influenza approaching the activity of standard antibiotic Azithromycin. Amidine derivatives with alkyl end groups appeared to be more active than their counterparts containing unsubstituted amidine moiety or cyclic amidines as end groups .…”

Section: Introductionmentioning

confidence: 90%

Thiophene Scaffold as Prospective Antimicrobial Agent: A Review

Mishra

Sachan

Kumar

et al. 2018

Journal of Heterocyclic Chem

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Thiophene has emerged as a potent scaffold that has pulled the keen interest of the researchers because of its considerable diversity in biological activities. The versatility of the thiophene nucleus is demonstrated by the successful introduction of its derivatives, which have anti‐inflammatory (Thenaldine), anticancer (Ralitrexed), antioxidant (Erdosteine), and antimicrobial (Cefoxitin and Temocillin) activities. This decent variety in the biological response profile has pulled in the consideration of numerous researchers to research this skeleton to its distinctive potential against several activities. This review is integral to prior reviews and plans to review the work regarding antibacterial and antifungal activities of thiophene, substituted thiophene and thiophene‐like compounds, and also Schiff bases of thiophene and substituted thiophenes from year 1995 to the beginning of 2018.

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“…The synthesis and physical properties of asymmetrical compounds 19e27 were given earlier [7] and theirs antitumor activity is described in the present study. Structural details of all studied molecules are shown in Fig.…”

Section: Compoundsmentioning

confidence: 99%

Antitumor activity of 3,4-ethylenedioxythiophene derivatives and quantitative structure-activity relationship analysis

Jukić

Rastija

Opačak-Bernardi

et al. 2017

Journal of Molecular Structure

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Synthesis and structure–activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents

Cited by 26 publications

References 56 publications

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Thiophene Scaffold as Prospective Antimicrobial Agent: A Review

Antitumor activity of 3,4-ethylenedioxythiophene derivatives and quantitative structure-activity relationship analysis

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