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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.

Aim. To reveal the prospects of the search of novel medicinal substances based on the studies of the derivatives of thieno[2,3-d]pyrimidine with the carboxylic groups as the substituents in the pyrimidine ring using the analysis of the published literature data.

Results and discussion. The study has shown a wider range of the pharmacological activity of thieno[2,3-d]pyrimidine-2-carboxylic acid derivatives compared to thieno[2,3-d]pyrimidine-4-carboxylic acids, as well as their availability, despite the fact that the number of preparative methods for the synthesis of these substances is rather limited. The most popular method is cyclization of 2-aminothiophene-3-carboxylic acids with ethyl cyanoformate. On the other hand, thieno[2,3-d]pyrimidine-4-carboxylic acid derivatives are presented in even fewer studies and are poorly studied; many of them are difficult to be synthesized and practically are not found in the pharmacological patent literature.

Conclusions. The literature data analysis has revealed the small number of efficient synthetic methods suitable for preparation of thieno[2,3-d]pyrimidines with the carboxylic groups as the substituents in the pyrimidine ring, as well as their low availability for the pharmacological studies. It is also noteworthy that the derivatives of thieno[2,3-d]pyrimidine-4-carboxylic acids are even less studied than the related compounds of thieno[2,3-d]pyrimidine-2-carboxylic acid series, and therefore, more attention should be paid to them as the objects for experimental chemistry and pharmacology.

Received: 12.08.2020
Revised: 23.09.2020
Accepted: 08.10.2020