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Article

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

1
Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002 Kharkiv, Ukraine
2
Enamine Ltd., 78 Chervonotkatska St., 02094 Kyiv, Ukraine
3
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., 02660 Kyiv, Ukraine
*
Author to whom correspondence should be addressed.
Academic Editor: Roman B. Lesyk
Sci. Pharm. 2021, 89(4), 49; https://doi.org/10.3390/scipharm89040049
Received: 23 October 2021 / Revised: 14 November 2021 / Accepted: 16 November 2021 / Published: 18 November 2021
(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)
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. View Full-Text
Keywords: thieno[2,3-d]pyrimidine; antimicrobial activity; TrmD inhibitor; docking study; Pseudomonas aeruginosa thieno[2,3-d]pyrimidine; antimicrobial activity; TrmD inhibitor; docking study; Pseudomonas aeruginosa
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MDPI and ACS Style

Vlasov, S.V.; Vlasova, O.D.; Severina, H.I.; Krolenko, K.Y.; Borysov, O.V.; Abu Sharkh, A.I.M.; Vlasov, V.S.; Georgiyants, V.A. 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. Sci. Pharm. 2021, 89, 49. https://doi.org/10.3390/scipharm89040049

AMA Style

Vlasov SV, Vlasova OD, Severina HI, Krolenko KY, Borysov OV, Abu Sharkh AIM, Vlasov VS, Georgiyants VA. 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. Scientia Pharmaceutica. 2021; 89(4):49. https://doi.org/10.3390/scipharm89040049

Chicago/Turabian Style

Vlasov, Sergiy V., Olena D. Vlasova, Hanna I. Severina, Konstantin Y. Krolenko, Oleksandr V. Borysov, Amjad I.M. Abu Sharkh, Vitaliy S. Vlasov, and Victoriya A. Georgiyants 2021. "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" Scientia Pharmaceutica 89, no. 4: 49. https://doi.org/10.3390/scipharm89040049

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