Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidines
The rapid development in bacterial resistance to many groups of known antibiotics forces the researchers to discover antibacterial drug candidates with previously unknown mechanisms of action, one of the most relevant being the inhibition of tRNA (Guanine37-N1)-methyltransferase (TrmD). The discover...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Scientia Pharmaceutica |
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| Online Access: | https://www.mdpi.com/2218-0532/89/4/49 |
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| author | Sergiy V. Vlasov Olena D. Vlasova Hanna I. Severina Konstantin Yu. Krolenko Oleksandr V. Borysov Amjad Ibrahim M. Abu Sharkh Vitaliy S. Vlasov Victoriya A. Georgiyants |
| author_facet | Sergiy V. Vlasov Olena D. Vlasova Hanna I. Severina Konstantin Yu. Krolenko Oleksandr V. Borysov Amjad Ibrahim M. Abu Sharkh Vitaliy S. Vlasov Victoriya A. Georgiyants |
| author_sort | Sergiy V. Vlasov |
| collection | DOAJ |
| description | The rapid development in bacterial resistance to many groups of known antibiotics forces the researchers to discover antibacterial drug candidates with previously unknown mechanisms of action, one of the most relevant being the inhibition of tRNA (Guanine37-N1)-methyltransferase (TrmD). The discovery of selective TrmD inhibitors in the series of carboxamide derivatives of thienopyrimidines became a background for further modification of the similar structures aimed at the development of promising antibacterial agents. As part of this research, we carried out the construction of heterocyclic hybrids bearing the moieties of thieno[2,3-<i>d</i>]pyrimidine and benzimidazole starting from 3,5-dimethyl-4-oxo-2-thioxo-1<i>H</i>-thieno[2,3-<i>d</i>]pyrimidine-6-carboxylic acid, which was used as the pivotal intermediate. The hybrid molecule of 6-(1<i>H</i>-benzimidazol-2-yl)-3,5-dimethyl-2-thioxo-1<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one prepared via condensation of the carboxylic acid with <i>ortho</i>-phenylenediamine was further alkylated with aryl/hetaryl chloroacetamides and benzyl chloride to produce the series of <i>S</i>-alkyl derivatives. The results of molecular docking studies for the obtained series of <i>S</i>-alkyl benzimidazole-thienopyrimidines showed their high affinity to the TrmD isolated from the <i>P. aeruginosa</i>. The results of antimicrobial activity screening revealed the antimicrobial properties for all of the studied molecules against both Gram-positive and Gram-negative bacteria and the <i>Candida albicans</i> fungal strain. The highest antimicrobial activity was determined for 2-{[6-(1<i>H</i>-benzimidazol-2-yl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidin-2-yl]thio}-<i>N</i>-(4-isopropylphenyl)acetamide, which also had the highest affinity to the TrmD inhibitor’s binding site according to the docking studies results. |
| first_indexed | 2024-03-10T03:11:07Z |
| format | Article |
| id | doaj.art-ec428ac290d44c679fa4056cb4cd25c3 |
| institution | Directory Open Access Journal |
| issn | 0036-8709 2218-0532 |
| language | English |
| last_indexed | 2024-03-10T03:11:07Z |
| publishDate | 2021-11-01 |
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| series | Scientia Pharmaceutica |
| spelling | doaj.art-ec428ac290d44c679fa4056cb4cd25c32023-11-23T10:27:34ZengMDPI AGScientia Pharmaceutica0036-87092218-05322021-11-018944910.3390/scipharm89040049Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidinesSergiy V. Vlasov0Olena D. Vlasova1Hanna I. Severina2Konstantin Yu. Krolenko3Oleksandr V. Borysov4Amjad Ibrahim M. Abu Sharkh5Vitaliy S. Vlasov6Victoriya A. Georgiyants7Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, UkraineDepartment of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, UkraineDepartment of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, UkraineEnamine Ltd., 78 Chervonotkatska St., 02094 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska St., 02094 Kyiv, UkraineDepartment of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, UkraineDepartment of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, UkraineDepartment of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, UkraineThe rapid development in bacterial resistance to many groups of known antibiotics forces the researchers to discover antibacterial drug candidates with previously unknown mechanisms of action, one of the most relevant being the inhibition of tRNA (Guanine37-N1)-methyltransferase (TrmD). The discovery of selective TrmD inhibitors in the series of carboxamide derivatives of thienopyrimidines became a background for further modification of the similar structures aimed at the development of promising antibacterial agents. As part of this research, we carried out the construction of heterocyclic hybrids bearing the moieties of thieno[2,3-<i>d</i>]pyrimidine and benzimidazole starting from 3,5-dimethyl-4-oxo-2-thioxo-1<i>H</i>-thieno[2,3-<i>d</i>]pyrimidine-6-carboxylic acid, which was used as the pivotal intermediate. The hybrid molecule of 6-(1<i>H</i>-benzimidazol-2-yl)-3,5-dimethyl-2-thioxo-1<i>H</i>-thieno[2,3-<i>d</i>]pyrimidin-4-one prepared via condensation of the carboxylic acid with <i>ortho</i>-phenylenediamine was further alkylated with aryl/hetaryl chloroacetamides and benzyl chloride to produce the series of <i>S</i>-alkyl derivatives. The results of molecular docking studies for the obtained series of <i>S</i>-alkyl benzimidazole-thienopyrimidines showed their high affinity to the TrmD isolated from the <i>P. aeruginosa</i>. The results of antimicrobial activity screening revealed the antimicrobial properties for all of the studied molecules against both Gram-positive and Gram-negative bacteria and the <i>Candida albicans</i> fungal strain. The highest antimicrobial activity was determined for 2-{[6-(1<i>H</i>-benzimidazol-2-yl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidin-2-yl]thio}-<i>N</i>-(4-isopropylphenyl)acetamide, which also had the highest affinity to the TrmD inhibitor’s binding site according to the docking studies results.https://www.mdpi.com/2218-0532/89/4/49thieno[2,3-<i>d</i>]pyrimidineantimicrobial activityTrmD inhibitordocking study<i>Pseudomonas aeruginosa</i> |
| spellingShingle | Sergiy V. Vlasov Olena D. Vlasova Hanna I. Severina Konstantin Yu. Krolenko Oleksandr V. Borysov Amjad Ibrahim M. Abu Sharkh Vitaliy S. Vlasov Victoriya A. Georgiyants Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidines Scientia Pharmaceutica thieno[2,3-<i>d</i>]pyrimidine antimicrobial activity TrmD inhibitor docking study <i>Pseudomonas aeruginosa</i> |
| title | Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidines |
| title_full | Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidines |
| title_fullStr | Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidines |
| title_full_unstemmed | Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidines |
| title_short | Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1<i>H</i>-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-<i>d</i>]pyrimidines |
| title_sort | design synthesis and in vitro antimicrobial activity of 6 1 i h i benzimidazol 2 yl 3 5 dimethyl 4 oxo 2 thio 3 4 dihydrothieno 2 3 i d i pyrimidines |
| topic | thieno[2,3-<i>d</i>]pyrimidine antimicrobial activity TrmD inhibitor docking study <i>Pseudomonas aeruginosa</i> |
| url | https://www.mdpi.com/2218-0532/89/4/49 |
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