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.

Syntheses of 3-(4-arylthieno[2,3- d ]pyrimidin-2-yl)-2 H -chromen-2-ones 5 by the reaction of 2-iminocoumarin-3-carboxamides 1 with (2-aminothiophen-3-yl)(aryl)methanones 2 and by the alternative Suzuki coupling of 4-chlorothieno[2,3- d ]pyrimidin-2-yl-2 H -chromen-2-one 7 with arylboronic acids were developed. Compound 5d showed higher antimicrobial activity against Staphylococcus aureus than the reference drug streptomycin.

The methods for the synthesis of the substituted arylamides of 4-(4-oxo-4H-quinazolin-3-yl)-piperidine-1-carboxylic acids using the technologies of the liquid-phase parallel synthesis have been developed. The structure of the compounds obtained has been confi rmed by the data of the instrumental methods of organic analysis. The antibacterial activity of the compounds obtained has been studied using the agar “well” diffusion method against the standard test-strains of microorganisms. The results of the screening performed have shown that all compounds inhibit the growth of Staphylococcus aureus and Bacillus subtilis strains. The strains of Proteus vulgaris and Pseudomonas aeruginosa have been found to be the most resistant. The SAR-analysis of the substituted arylamides of 4-(4-oxo-4H-quinazolin-3-yl)-piperidine-1-carboxylic acids has demonstrated that the presence of the electron-donating substituents in position 8 of the quinazolin-4-one cycle and in position 4 of the aromatic fragment of the urea increases the activity of the compounds of this series against gram-positive bacteria. Such high effi cacy of the lead compounds against the gram-positive bacterial strains can be applied for creating the narrow spectrum antibiotics derived from arylamides of 4-(4-oxo-4H-quinazolin-3-yl)-piperidine-1-carboxylic acids.