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

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

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 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