Novel 4-methylthienopyrimidines as antimicrobial agents: synthesis, docking study and in vitro evaluation

Sergiy Vlasov; Konstantin Krolenko; Hanna Severina; Olena Vlasova; Oleksandr Borysov; Pavlo Shynkarenko; Vitaliy Vlasov; Victoriya Georgiyants

doi:10.7324/JAPS.2023.102631

Abstract

Compounds with thieno[2,3-d]pyrimidine core modified with amide group at position five of the heterocyclic system were reported as ligands to bacterial TrmD, which is an enzyme responsible for protein synthesis in bacterial cells and its blockage leads to the death of bacteria or makes them less resistant to antibiotic therapy. The great problem of antibiotic resistance, especially of Gram-negative bacteria like Pseudomonas aeruginosa, forced us to design and study the antimicrobial properties of novel thieno[2,3-d]pyrimidine with amide function at position six as possible bacterial TrmD inhibitors. For the synthesis of the target derivatives with an aromatic pyrimidine cycle and a methyl group at position four, the Suzuki reaction was used. The previously unknown key intermediate 4,5-dimethylthieno[2,3-d] pyrimidine-6-carboxylic acid was further transformed into various novel derivatives of 4-methylthieno[2,3-d] pyrimidines by interaction with amines. The antimicrobial activity screening results show that benzyl amides of 4,5-dimethylthienopyrimidines were the most active, especially against Ba?illus subtilis and P. aeruginosa. The docking studies also revealed that benzylamides showed the best binding parameters to the selective inhibitors’ active site of tRNA (Guanine37-N1)-methyltransferase, an enzyme isolated from P. aeruginosa.

Keyword: Benzyl amides thienopyrimidine Suzuki reaction antimicrobial activity

Citation:

Vlasov S, Krolenko K, Severina H, Vlasova O, Borysov O, Shynkarenko ?, Vlasov V, Georgiyants V. Novel 4-methylthienopyrimidines as antimicrobial agents: synthesis, docking study and in vitro evaluation. J Appl Pharm Sci, 2022. https://doi.org/10.7324/JAPS.2023.102631

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reference

Ahmed Z, Saeed Khan S, Khan M. In vitro trials of some antimicrobial combinations against Staphylococcus aureus and Pseudomonas aeruginosa. Saudi J Biol Sci, 2013; 20(1):79-83. https://doi.org/10.1016/j.sjbs.2012.10.005

Badiger NP, Gaonkar SL, Shetty NS. Synthesis of some new thienopyrimidines and triazole fused thienopyrimidines and their antimicrobial activities. Internat J Chem Pharm Sci, 2015; 6(1):58-62.

Brown DG, Wobst HJ. A decade of FDA-approved drugs (2010- 2019): trends and future directions. J Med Chem, 2021; 64(5):2312-38. https://doi.org/10.1021/acs.jmedchem.0c01516

Cercenado E. Espectro antimicrobiano de dalbavancina. Mecanismo de accion y actividad in vitro frente a microorganismos Gram positivos. Enferm Infecc Microbiol Clin, 2017; 35(1):9-14. https://doi.org/10.1016/S0213-005X(17)30029-0

Coyle MB. Manual of antimicrobial susceptibility testing. American Society for Microbiology, Washington, DC, 241 c p, 2005.

De Schutter JW, Morrison JP, Morrison MJ, Ciulli A, Imperiali B. Targeting Bacillosamine biosynthesis in bacterial pathogens: development of inhibitors to a bacterial amino-sugar acetyltransferase from Campylobacter jejuni. J Med Chem, 2017; 60(5):2099-118. https://doi.org/10.1021/acs.jmedchem.6b01869

El-Gamal M, Kim S, Oh CH. Synthesis and in vitro antibacterial activity of new meropenem analogs. J Antibiot, 2011; 64:687-8. https://doi.org/10.1038/ja.2011.70

Falb E, Ulanenko K, Tor A, Gottesfeld R, Weitman M, Afri M, Gottlieb HE, Hassner A. A highly efficient Suzuki-Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560). Green Chem, 2017; 19:5046-53. https://doi.org/10.1039/C7GC01740E

Fernandez-Mato A, Peinador C, Quintal JM. Convenient one-pot synthesis of functionalized thieno[3,2-d]pyrimidine and thieno[2,3-d] pyrimidine derivatives. Synthesis, 2011; (20):3323-31. https://doi.org/10.1055/s-0030-1260217

Gamper HB, Masuda I, Frenkel-Morgenstern M, Hou YM. Maintenance of protein synthesis reading frame by EF-P and m(1)G37- tRNA. Nat Commun, 2015; 6:7226. https://doi.org/10.1038/ncomms8226

Goto-Ito S, Ito T, Yokoyama S. Trm5 and TrmD: two enzymes from distinct origins catalyze the iIdentical tRNA modification, m¹G37. Biomolecules, 2017; 7(1):32. https://doi.org/10.3390/biom7010032

Hill PJ, Abibi A, Albert R, Andrews B, Gagnon MM, Gao N, Grebe T, Hajec LI, Huang J, Livchak S, Lahiri SD, McKinney DC, Thresher J, Wang H, Olivier N, Buurman ET. Selective inhibitors of bacterial t-RNA- (N(1)G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain. J Med Chem, 2013; 56(18):7278-88. https://doi.org/10.1021/jm400718n

Jansen G, Mahrt N, Tueffers L, Barbosa C, Harjes M, Adolph G, Friedrichs A, Krenz-Weinreich A, Rosenstiel P, Schulenburg H. Association between clinical antibiotic resistance and susceptibility of Pseudomonas in the cystic fibrosis lung. Evol Med Public Health, 2016; 2016(1):182-94. https://doi.org/10.1093/emph/eow016

Jones F, Hu Y, Coates A. The efficacy of using combination therapy against multi-drug and extensively drug-resistant Pseudomonas aeruginosa in clinical settings. Antibiotics (Basel), 2022; 11(3):323. https://doi.org/10.3390/antibiotics11030323

Karroum NB, Patinote C, Deleuze-Masquefa C, Moarbess G, Diab-Assaf M, Cuq P, Kassab I. Methylation of imidazopyrazine, imidazoquinoxaline, and pyrazoloquinoxaline through Suzuki-Miyaura cross coupling. Chem Heterocyc Comp, 2018; 54(2):183-7. https://doi.org/10.1007/s10593-018-2252-8

Khan M, Stapleton F, Summers S, Rice SA, Willcox MDP. Antibiotic resistance characteristics of Pseudomonas aeruginosa isolated from keratitis in Australia and India. Antibiotics (Basel), 2020; 9(9):600. https://doi.org/10.3390/antibiotics9090600

Lin S, Wang C, Ji M, Wu D, Lv Y, Sheng L, Han F, Dong Y, Zhang K, Yang Y, Li Y, Chen X, Xu H. Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors. Bioorg Med Chem, 2018; 26(3):637-46. https://doi.org/10.1016/j.bmc.2017.12.025

Magaldi S, Mata-Essayag S, Hartung de Capriles C, Perez C, Colella MT, Olaizola C, Ontiveros Y. Well diffusion for antifungal susceptibility testing. Int J Infect Dis, 2004; 8(1)39-45. https://doi.org/10.1016/j.ijid.2003.03.002

Malasala S, Polomoni A, Ahmad Md N, Shukla M, Kaul G, Dasgupta A, Chopra S, Nanduri S. Structure based design, synthesis and evaluation of new thienopyrimidine derivatives as anti-bacterial agents. J Molec Struct, 2021; 1234:130168. https://doi.org/10.1016/j.molstruc.2021.130168

Manhas MS, Sharma SD. Hetcrocyclic compounds III. Synthesis of some substituted thienopyrimidines. J Heterocyc Chem, 1971; 8:1051-3. https://doi.org/10.1002/jhet.5570080633

Masuda I, Matsubara R, Christian T, Rojas ER, Yadavalli SS, Zhang L, Goulian M, Foster LJ, Huang KC, Hou YM. tRNA methylation Is a global determinant of dacterial multi-drug resistance. Cell Syst, 2019; 8(4):302-14.e8. https://doi.org/10.1016/j.cels.2019.03.008

McFarland J. The nephelometer: an instrument for estimating the number of bacteria in suspensions used for calculating the opsonic index and for vaccines. J A Med Assoc, 1907; 49(14):1176-8. https://doi.org/10.1001/jama.1907.25320140022001f

Ministry of Public Health of Ukraine (MHU). Bacteriological control of culture media; Newsletter ? 05.4.1/1670. Ministry of Public Health of Ukraine, Kiev, Ukraine, 45 p, 2001.

Mitra S, Saeed U, Havlichek DH, Stein GE. Profile of oritavancin and its potential in the treatment of acute bacterial skin structure infections. Infect Drug Resist, 2015; 8:189-97. https://doi.org/10.2147/IDR.S69412

Nekrasova LS, Svita VM, Glushkevich TG, Tomchuk VV, Zherebko NM, Yanovs'ka VV. Methodological guidelines "Determination of the Sensitivity of Microorganisms to Antibiotics"; ? MB 9.9.5-143- 2007. Ministry of Public Health of Ukraine, Kiev, Ukraine, 24 p, 2007.

Olsson A, Wistrand-Yuen P, Nielsen EI, Friberg LE, Sandegren L, Lagerbäck P, Tängdén T. Efficacy of antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa in automated time-lapse microscopy and static time-kill experiments. Antimicrob Agents Chemother, 2020; 64(6):e02111-9. https://doi.org/10.1128/AAC.02111-19

Pang Z, Raudonis R, Glick BR, Lin TJ, Cheng Z. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Biotechnol Adv, 2019; 37(1):177-92; doi:10.1016/j. biotechadv.2018.11.013 https://doi.org/10.1016/j.biotechadv.2018.11.013

Protein Data Bank. Available via http://www.rcsb.org/pdb/home/ home.do (Accessed 10 April 2022).

Richter MF, Drown BS, Riley AP, Garcia A, Shirai T, Svec RL, Hergenrother PJ. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature, 2017; 545(7654):299-304. https://doi.org/10.1038/nature22308

Sakamoto T, Kondo Y, Watanabe R, Yamanaka H. Condensed heteroaromatic ring systems. VII: synthesis of thienopyridines, thienopyrimidines, and furopyridines from o-substituted N-heteroarycetylenes. Chem Pharm Bull, 1986; 34(7):2719-24. https://doi.org/10.1248/cpb.34.2719

Severina HI, Skupa OO, Voloshchuk NI, Georgiyants VA. Synthesis, docking study, and pharmacological evaluation of S-acetamide derivatives of 4,6-dimethyl-2-thiopyrimidine as anticonvulsant agents. J Appl Pharm S, 2020; 10(07):001-8. https://doi.org/10.7324/JAPS.2020.10701

Tereshko V, Skripkin E, Patel DJ. Encapsulating streptomycin within a small 40-mer RNA. Chem Biol, 2003; 10(2):175-87. https://doi.org/10.1016/S1074-5521(03)00024-3

Therkelsen FD, Rottlaender M, Thorup N, Bjerregaard PE. 4-Metalated condensed pyrimidines: their preparation and reaction with aldehydes under barbier-type conditions. Org Lett, 2004; 6(12):1991-4. https://doi.org/10.1021/ol049432v

Tommasi R, Brown DG, Walkup GK, Manchester JI, Miller AA. ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov, 2015; 14(8):529-42. https://doi.org/10.1038/nrd4572

Torres PHM, Sodero ACR, Jofily P, Silva-Jr FP. Key topics in molecular docking for drug design. Int J Mol Sci, 2019; 20(18):4574-603. https://doi.org/10.3390/ijms20184574

Triloknadh S, Venkata Rao C, Nagaraju K, Hari Krishna N, Venkata Ramaiah C, Rajendra W, Trinath D, Suneetha Y. Design, synthesis, neuroprotective, antibacterial activities and docking studies of novel thieno[2,3-d]pyrimidine-alkyne Mannich base and oxadiazole hybrids. Bioorg Med Chem Lett, 2018; 28(9):1663-9. https://doi.org/10.1016/j.bmcl.2018.03.030

Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P & T, 2015; 40(4):277-83.

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. Sci Pharm, 2021; 89(4):49. https://doi.org/10.3390/scipharm89040049

Vlasov SV, Severina HI, Borysov OV, Krolenko KY, Shynkarenko PE, Saidov NB, Vlasov VS, Georgiyants VA. 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. Molbank, 2022; 1:M1331. https://doi.org/10.3390/M1331

Vlasova OD, Krolenko KYu, Nechayev MA, Shynkarenko PE, Kabachnyy VI, Vlasov SV. Efficient method for the synthesis of novel substituted thieno[2,3-d]pyrimidine-4-carboxylic acids, their derivatization, and antimicrobial activity. Chem Heterocycl Comp, 2019; 55(2):184-8. https://doi.org/10.1007/s10593-019-02437-1

Wagenlehner FME, Cloutier DJ, Komirenko AS, Cebrik DS, Krause KM, Keepers TR, Connolly LE, Miller LG, Friedland I, Dwyer JP. Once-daily Plazomicin for complicated urinary tract infections. New Engl J Med, 2019; 380(8):729-40. https://doi.org/10.1056/NEJMoa1801467

Whitehouse AJ, Thomas SE, Brown KP, Fanourakis A, Chan DS, Libardo MDJ, Mendes V, Boshoff HIM, Floto RA, Abell C, Blundell TL, Coyne AG. Development of inhibitors against Mycobacterium abscessus tRNA (m1G37) methyltransferase (TrmD) using fragment-based approaches. J Med Chem, 2019; 62(15):7210-32. https://doi.org/10.1021/acs.jmedchem.9b00809

Yakout MA, Abdelwahab IA. Diabetic foot ulcer infections and Pseudomonas aeruginosa biofilm production during the COVID-19 pandemic. J Pure Appl Microbiol, 2022; 16(1):138-46. https://doi.org/10.22207/JPAM.16.1.02

Zhang G, Meredith, TC, Kahne D. On the essentiality of lipopolysaccharide to Gram-negative bacteria. Curr Opin Microbiol, 2013; 16(6):779-85. https://doi.org/10.1016/j.mib.2013.09.007

ZhongW, Koay A, Ngo A, Li Y, Nah Q, Wong YH, Chionh YH, Ng HQ, Koh-Stenta X, Poulsen A, Foo K, McBee M, Choong ML, El Sahili A, Kang C, Matter A, Lescar J, Hill J, Dedon P. Targeting the bacterial epitranscriptome for antibiotic development: discovery of novel tRNA- (N1G37) methyltransferase (TrmD) inhibitors. ACS Infect Dis, 2019a; 5(3):326-35. https://doi.org/10.1021/acsinfecdis.8b00275

Abstract

HTML Full Text

Reference

Article Metrics

Related Search

Citiaion Alert By Google Scholar

Similar Articles