Synthesis and Biological Activity of 6-(1,3-Benzoxazol-2-Yl)-5-Methylthieno-[2,3-d]Pyrimidines

Vlasov, Sergiy V.; Kovalenko, Sergiy M.; Осолодченко, Т. П.; Lenitskaya, E. B.; Chernykh, V. P.

doi:10.1007/s11094-018-1850-1

Cited by 5 publications

(5 citation statements)

References 8 publications

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“…Taking into account the positive results of our previous research on the regioselectivity of the alkylation of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one with benzyl chlorides [3], as well as some successful experience of the transfer of the method developed for benzyl chlorides to chloroacetamides for the similar systems with the fragment of 5-methylthieno [2,3-d]pyrimidin-4(3H)-one [4] we decided to do the same for benzimidazole containing derivatives. The starting compound 1 obtained according to the method previously reported [3] was treated with either N-arylchloroacetamides or 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles in the DMF media using the equimolar amount of potassium carbonate to promote the reaction (Scheme).…”

Section: Resultsmentioning

confidence: 99%

“…Earlier different preparation methods for these compounds were reported [1 -3], and the selectivity of their alkylation with benzyl chlorides was studied [3]. The works published in recent years has also shown the positive impact of the acetamide or isoxadiazole substituent in position 3 of thieno [2,3-d]pyrimidine on the antimicrobial activity [4,5]. The substitution of other positions of the core heterocyclic structure with 1,2,4oxadiazole was also effective for improving the antimicrobial activity [6 -9].…”

Section: Introductionmentioning

confidence: 99%

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The synthesis, antimicrobial activity and docking studies of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin- 4(3H)-ones with acetamide and 1,2,4-oxadiazol-5-ylmethyl substituents

Vlasov

Borysov

Severina

et al. 2021

J. org. pharm. chem.

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Aim. To synthesize, study the antimicrobial activity and suggest antimicrobial activity mechanism for the novel derivatives of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one. Results and discussion. As the result of the targeted modification of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]-pyrimidin-4(3H)-one in position 3 with acetamide and 1,2,4-oxadiazol-5-ylmethyl substituents, the compounds, which demonstrated better antimicrobial activity in the agar well diffusion assay than the reference drug Streptomycin, were obtained. To elucidate the mechanism of action of the novel compounds, the docking studies were con-ducted to the active site of the 16S subunit of ribosomal RNA, the proven target for aminoglycoside antibiotics, as well as tRNA (Guanine37-N1)-methyltransferase (TrmD), which inhibitors were considered as a new potential class of antibiotics. Experimental part. By the interaction of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one with a series of N-arylchloroacetamides and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles in DMF in the presence of K2CO3 the target compounds were obtained. The antimicrobial activity was assessed by the agar well diffusion method. The concentration of microbial cells was determined by the McFarland standard; the value was 107 cells in 1 mL of the media. The 18 – 24 hour culture of microorganisms was used for tests. For the bacteria cultivation, Müller-Hinton agar was used, Sabouraud agar was applied for C. albicans cultivation. The compounds were tested as the DMSO solution with the concentration of 100 µg/mL; the volume of the solution was 0.3 mL, the same volume was used for Streptomycin (the concentration 30 µg/mL). The docking studies were performed using Autodock Vina. Crystallographic data for the complexes of Streptomycin with the 16S subunit of ribosomal RNA (1NTB) and its active site, as well as for tRNA (Guanine37-N1)-methyltransferase (EC 2.1.1.228; TrmD) (5ZHN) and its active site were obtained from the Protein Data Bank.Conclusions. It has been determined that 2-[6-(1H-benzimidazol-2-yl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl]-N-[4-(ethoxy)phenyl]acetamide, which is the most active as an antimicrobial agent among the compounds tested, also shows the best binding activity towards the active site of tRNA (guanine37-N1)-methyltransferase.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The synthesis, antimicrobial activity and docking studies of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin- 4(3H)-ones with acetamide and 1,2,4-oxadiazol-5-ylmethyl substituents

Vlasov

Borysov

Severina

et al. 2021

J. org. pharm. chem.

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“…Likewise, numerous articles have been published in the last decade about the antimicrobial activity of 6-heterylthieno [2,3-d]pyrimidines with unsubstituted position 2 [4][5][6][7] (II-V) (Figure 1), some of them containing fused systems of heterocycles such as 1,2,4triazolo [3,4-b]1,3,4-thiadiazole (III) [5] or 1,3-benzoxazole (V) [7]. One of the latest works published was devoted to the study of the antimicrobial activity of 6-heteryl-5-methyl-2thiothieno [2,3-d]pyrimidines, which can possibly act as inhibitors of bacterial TrmD VI (Figure 1) [8].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimicrobial Evaluation of 2-(6-Imidazo[1,2-a]pyridin-2-yl-5-methyl-2,4-dioxo-3-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)-N-arylacetamide Derivatives

Vlasov

Severina

Borysov

et al. 2022

Molbank

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6-Heteryl-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-diones are of great interest as the promising objects for the search of antibacterials. In this communication, we obtained 6-(imidazo[1,2-a]pyridin-2-yl)-5-methyl-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione by interaction of 6-(bromoacetyl)-5-methyl-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione with 2-aminopyridine. The obtained heterocyclic hybrid was further modified by alkylation with 2-chloroarylacetamides. Antimicrobial activity studies for the synthesized compounds using the agar well diffusion method revealed their moderate activity against S. aureus, E. coli and B. subtilis. According to the double dilution assay MIC value results for 6-(imidazo[1,2-a]pyridin-2-yl)-5-methyl-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneagainst P. aeruginosa was less than the value determined for the reference drug streptomycin. The docking study of the synthesized compounds to the active site of TrmD isolated from P. aeruginosa did not show their effective inhibitory activity.

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“…In the last decade, we largely studied the antimicrobial activity of different synthetically prepared thieno [2,3-d]pyrimidines. The highest antimicrobial activity against Gramnegative bacteria (and P. aeruginosa in particular) was determined for 6-heterylthieno [2,3d]pyrimidines with 1,3,4-oxadiazole I (Figure 1) [6], 2-aminothiazole II [7] and 1,3-benzoxazole moieties attached to thieno [2,3-d]pyrimidin-4-one or 4-thione moieties III [8]. The successful application of the hybrid pharmacophore concept achieved by the combination of thieno [2,3-d]pyrimidine with the other heterocycles has been reported by many other scientific groups.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1H-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-d]pyrimidines

et al. 2021

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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-d]pyrimidine and benzimidazole starting from 3,5-dimethyl-4-oxo-2-thioxo-1H-thieno[2,3-d]pyrimidine-6-carboxylic acid, which was used as the pivotal intermediate. The hybrid molecule of 6-(1H-benzimidazol-2-yl)-3,5-dimethyl-2-thioxo-1H-thieno[2,3-d]pyrimidin-4-one prepared via condensation of the carboxylic acid with ortho-phenylenediamine was further alkylated with aryl/hetaryl chloroacetamides and benzyl chloride to produce the series of S-alkyl derivatives. The results of molecular docking studies for the obtained series of S-alkyl benzimidazole-thienopyrimidines showed their high affinity to the TrmD isolated from the P. aeruginosa. 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 Candida albicans fungal strain. The highest antimicrobial activity was determined for 2-{[6-(1H-benzimidazol-2-yl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl]thio}-N-(4-isopropylphenyl)acetamide, which also had the highest affinity to the TrmD inhibitor’s binding site according to the docking studies results.

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Synthesis and Biological Activity of 6-(1,3-Benzoxazol-2-Yl)-5-Methylthieno-[2,3-d]Pyrimidines

Cited by 5 publications

References 8 publications

The synthesis, antimicrobial activity and docking studies of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin- 4(3H)-ones with acetamide and 1,2,4-oxadiazol-5-ylmethyl substituents

The synthesis, antimicrobial activity and docking studies of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin- 4(3H)-ones with acetamide and 1,2,4-oxadiazol-5-ylmethyl substituents

Synthesis and Antimicrobial Evaluation of 2-(6-Imidazo[1,2-a]pyridin-2-yl-5-methyl-2,4-dioxo-3-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)-N-arylacetamide Derivatives

Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1H-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-d]pyrimidines

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