Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its Derivatives
The antitumor drug 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ (<b>1</b>)) along with a number of newly synthesized tirapazamine derivatives (TPZs) bearing substitutions at the 3-amine position of TPZ (<b>1</b>) were estimated for their antibacterial activity a...
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MDPI AG
2020-06-01
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| author | Evelina Polmickaitė-Smirnova Jonas Šarlauskas Kastis Krikštopaitis Živilė Lukšienė Zita Staniulytė Žilvinas Anusevičius |
| author_facet | Evelina Polmickaitė-Smirnova Jonas Šarlauskas Kastis Krikštopaitis Živilė Lukšienė Zita Staniulytė Žilvinas Anusevičius |
| author_sort | Evelina Polmickaitė-Smirnova |
| collection | DOAJ |
| description | The antitumor drug 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ (<b>1</b>)) along with a number of newly synthesized tirapazamine derivatives (TPZs) bearing substitutions at the 3-amine position of TPZ (<b>1</b>) were estimated for their antibacterial activity against representative Gram-negative <i>Escherichia coli</i> (ATCC 25922) and <i>Salmonella enterica</i> (SL 5676), as well as Gram-positive <i>Staphylococcus aureus</i> (ATCC 25923) bacterial strains. Their activities in terms of minimum inhibitory concentrations (MICs) varied in the range of 1.1 µM (0.25 µg/mL)–413 µM (128 µg/mL). Amongst the most potent derivatives (<b>1</b>–<b>6</b>), acetyl- and methoxycarbonyl-substituted TPZs (<b>2</b> and <b>4</b>) were the strongest agents, which exhibited approximately 4–30 fold greater activities compared to those of TPZ (<b>1</b>) along with the reference drugs chloramphenicol (CAM) and nitrofurantoin (NFT). The inhibitory activities of the compounds were highly impacted by their structural features. No reliable relationships were established between activities and the electron-accepting potencies of the whole set of studied compounds, while the activities of TPZ drug (<b>1</b>) and the structurally uniform set of molecules (<b>2</b>–<b>6</b>) were found to increase with an increase in their electron-accepting potencies obtained by means of density functional theory (DFT) computation. A greater steric, lipophilic and polar nature of the substituents led to a lower activity of the compounds. The combined antibacterial <i>in vitro</i> trial gave clear evidence that TPZs coupled with the commonly utilized antibiotics ciprofloxacin (Cipro) and nitrofurantoin (NFT) could generate enhanced (suggestive of partial and virtually complete synergistic) and additive effects. The strongest effects were defined for TPZs–NFT combinations, which resulted in a notable reduction in the MICs of di-<i>N</i>-oxides. These preliminary findings suggest that the synthesized novel di-<i>N</i>-oxides might be used as sole agents or applied as antibiotic complements. |
| first_indexed | 2024-03-10T19:12:39Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T19:12:39Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
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| spelling | doaj.art-00b6d7faf6014048b796cdbce74ee3162023-11-20T03:36:27ZengMDPI AGApplied Sciences2076-34172020-06-011012406210.3390/app10124062Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its DerivativesEvelina Polmickaitė-Smirnova0Jonas Šarlauskas1Kastis Krikštopaitis2Živilė Lukšienė3Zita Staniulytė4Žilvinas Anusevičius5Institute of Biochemistry, Life Science Center, Vilnius University, Saulėtekio av. 7, LT-10257 Vilnius, LithuaniaInstitute of Biochemistry, Life Science Center, Vilnius University, Saulėtekio av. 7, LT-10257 Vilnius, LithuaniaInstitute of Biochemistry, Life Science Center, Vilnius University, Saulėtekio av. 7, LT-10257 Vilnius, LithuaniaInstitute of Photonics and Nanotechnology, Vilnius University, Saulėtekio av. 10, LT-10223 Vilnius, LithuaniaInstitute of Biochemistry, Life Science Center, Vilnius University, Saulėtekio av. 7, LT-10257 Vilnius, LithuaniaInstitute of Biochemistry, Life Science Center, Vilnius University, Saulėtekio av. 7, LT-10257 Vilnius, LithuaniaThe antitumor drug 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ (<b>1</b>)) along with a number of newly synthesized tirapazamine derivatives (TPZs) bearing substitutions at the 3-amine position of TPZ (<b>1</b>) were estimated for their antibacterial activity against representative Gram-negative <i>Escherichia coli</i> (ATCC 25922) and <i>Salmonella enterica</i> (SL 5676), as well as Gram-positive <i>Staphylococcus aureus</i> (ATCC 25923) bacterial strains. Their activities in terms of minimum inhibitory concentrations (MICs) varied in the range of 1.1 µM (0.25 µg/mL)–413 µM (128 µg/mL). Amongst the most potent derivatives (<b>1</b>–<b>6</b>), acetyl- and methoxycarbonyl-substituted TPZs (<b>2</b> and <b>4</b>) were the strongest agents, which exhibited approximately 4–30 fold greater activities compared to those of TPZ (<b>1</b>) along with the reference drugs chloramphenicol (CAM) and nitrofurantoin (NFT). The inhibitory activities of the compounds were highly impacted by their structural features. No reliable relationships were established between activities and the electron-accepting potencies of the whole set of studied compounds, while the activities of TPZ drug (<b>1</b>) and the structurally uniform set of molecules (<b>2</b>–<b>6</b>) were found to increase with an increase in their electron-accepting potencies obtained by means of density functional theory (DFT) computation. A greater steric, lipophilic and polar nature of the substituents led to a lower activity of the compounds. The combined antibacterial <i>in vitro</i> trial gave clear evidence that TPZs coupled with the commonly utilized antibiotics ciprofloxacin (Cipro) and nitrofurantoin (NFT) could generate enhanced (suggestive of partial and virtually complete synergistic) and additive effects. The strongest effects were defined for TPZs–NFT combinations, which resulted in a notable reduction in the MICs of di-<i>N</i>-oxides. These preliminary findings suggest that the synthesized novel di-<i>N</i>-oxides might be used as sole agents or applied as antibiotic complements.https://www.mdpi.com/2076-3417/10/12/4062heterocyclic di-<i>N</i>-oxides1,2,4-benzotriazine di-<i>N</i>-oxidestirapazamine (TPZ)antibacterial activityminimum inhibitory concentrations (MICs)chloramphenicol |
| spellingShingle | Evelina Polmickaitė-Smirnova Jonas Šarlauskas Kastis Krikštopaitis Živilė Lukšienė Zita Staniulytė Žilvinas Anusevičius Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its Derivatives Applied Sciences heterocyclic di-<i>N</i>-oxides 1,2,4-benzotriazine di-<i>N</i>-oxides tirapazamine (TPZ) antibacterial activity minimum inhibitory concentrations (MICs) chloramphenicol |
| title | Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its Derivatives |
| title_full | Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its Derivatives |
| title_fullStr | Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its Derivatives |
| title_full_unstemmed | Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its Derivatives |
| title_short | Preliminary Investigation of the Antibacterial Activity of Antitumor Drug 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide (Tirapazamine) and its Derivatives |
| title_sort | preliminary investigation of the antibacterial activity of antitumor drug 3 amino 1 2 4 benzotriazine 1 4 dioxide tirapazamine and its derivatives |
| topic | heterocyclic di-<i>N</i>-oxides 1,2,4-benzotriazine di-<i>N</i>-oxides tirapazamine (TPZ) antibacterial activity minimum inhibitory concentrations (MICs) chloramphenicol |
| url | https://www.mdpi.com/2076-3417/10/12/4062 |
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