Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Microwave-assisted Synthesis and Docking Studies of Phenylureas as Candidates for the Drug Design Against the Biological Warfare Agent Yersinia Pestis

Author(s): Tanos Celmar Costa França*, Leonardo da Costa Bastos, Teobaldo Cuya, Mehdi Sirouspour, Franklin Chacón-Huete, David Bendahan and Pat Forgione*

Volume 17, Issue 5, 2020

Page: [633 - 639] Pages: 7

DOI: 10.2174/1570180816666190710144212

Abstract

Background: Bubonic plague is amongst the diseases with the highest potential for being used in biological warfare attacks today. This disease, caused by the bacterium Yersina pestis, is highly infectious and can achieve 100% of fatal victims when in its most dangerous form. Besides, there is no effective vaccine, and the chemotherapy available today against plague is ineffective if not administered at the beginning of the infection.

Objective: Willing to contribute for changing this reality we propose here new phenylureas as candidates for the drug design against plague meant to target the enzyme dihydrofolate reductase from Y. pestis (YpDHFR).

Methods: Seven phenylureas, four of them new, were synthesized, following synthetic routes adapted from procedures available in the literature, and using microwave irradiation. After, they were submitted to docking studies inside YpDHFR and human DHFR (HssDHFR) in order to check their potential as selective inhibitors.

Results: Our results revealed four new phenylureas and a new synthetic route for this kind of molecule using microwave irradiation. Also, our docking studies showed that these compounds are capable of binding to both HssDHFR and YpDHFR, with U1 - U4 and U23 showing more selectivity for HssDHFR and U7, U8 being more selective towards YpDHFR.

Conclusion: We reported the synthesis with good yields of seven phenylureas, following a simple and clean alternative synthetic route using microwave irradiation. Further molecular docking studies of our compounds suggested that two are capable of binding more selectivity to YpDHFR, qualifying as potential candidates for the drug design of new drugs against plague.

Keywords: Plague, Yersinia pestis, phenylureas, docking, YpDHFR, human DHFR.

« Previous Next »
Graphical Abstract

[1]
Cortopassi, W.A.; Ramalho, T.C.; Fraga, C.A.M.; Mangas, I.; Kuca, K.; Franca, T.C.C. Bubonic plague: Historical aspects and therapy. Mil. Med. Sci. Lett., 2015, 84(2), 67-75.
[http://dx.doi.org/10.31482/mmsl.2015.006]
[2]
Oliveira, A.A.; Rennó, M.N.; de Matos, C.A.S.; Bertuzzi, M.D.; Ramalho, T.C.; Fraga, C.A.M.; França, T.C.C. Molecular modeling studies of Yersinia pestis dihydrofolate reductase. J. Biomol. Struct. Dyn., 2011, 29(2), 351-367.
[http://dx.doi.org/10.1080/07391102.2011.10507390] [PMID: 21875154]
[3]
Bastos, Lda.C.; de Souza, F.R.; Guimarães, A.P.; Sirouspour, M.; Cuya Guizado, T.R.; Forgione, P.; Ramalho, T.C.; França, T.C.C. Virtual screening, docking, and dynamics of potential new inhibitors of dihydrofolate reductase from Yersinia pestis. J. Biomol. Struct. Dyn., 2016, 34(10), 2184-2198.
[http://dx.doi.org/10.1080/07391102.2015.1110832] [PMID: 26494420]
[4]
Bastos, L.D.C.; de Souza, F.R.; Pereira Souza, L.M.; Forgione, P.; Cuya, T.; de Alencastro, R.B.; Pimentel, A.S.; Celmar Costa França, T. Investigating the selectivity of potential new inhibitors of dihydrofolate reductase from Yersinia pestis designed by molecular modeling. J. Biomol. Struct. Dyn., 2019, 37(5), 1170-1176.
[http://dx.doi.org/10.1080/07391102.2018.1452796] [PMID: 29542379]
[5]
Maxwell, B.D.; Boye, O.G.; Ohta, K. The 14C, 13C and 15N syntheses of MON 37500, a sulfonylurea wheat herbicide. J. Labelled Comp. Radiopharm., 2005, 48, 397-406.
[http://dx.doi.org/10.1002/jlcr.934]
[6]
Burgdorf, L.T.; Carell, T. Synthesis, stability, and conformation of the formamidopyrimidine G DNA lesion. Chemistry, 2002, 8(1), 293-301.
[http://dx.doi.org/10.1002/1521-3765(20020104)8:1<293:AID-CHEM293>3.0.CO;2-L] [PMID: 11822460]
[7]
Goswami, S.; Jana, S.; Dey, S.; Adak, A.K. Microwave-expedited one-pot, two-component, solvent-free synthesis of functionalized pyrimidines. Aust. J. Chem., 2007, 60, 120-123.
[http://dx.doi.org/10.1071/CH06388]
[8]
de Oliveira Lopes, R.; Romeiro, N.C.; de Lima, C.K.; Louback da Silva, L.; de Miranda, A.L.; Nascimento, P.G.B.D.; Cunha, F.Q.; Barreiro, E.J.; Lima, L.M. Docking, synthesis and pharmacological activity of novel urea-derivatives designed as p38 MAPK inhibitors. Eur. J. Med. Chem., 2012, 54, 264-271.
[http://dx.doi.org/10.1016/j.ejmech.2012.05.006] [PMID: 22647219]
[9]
Antosiewicz, A.; Jarmuła, A.; Przybylska, D.; Mosieniak, G.; Szczepanowska, J.; Kowalkowska, A.; Rode, W.; Cieśla, J. Human dihydrofolate reductase and thymidylate synthase form a complex in vitro and co-localize in normal and cancer cells. J. Biomol. Struct. Dyn., 2017, 35(7), 1474-1490.
[http://dx.doi.org/10.1080/07391102.2016.1186560] [PMID: 27187663]
[10]
Hehre, W.J.; Deppmeier, B.J.; Klunzinger, P.E.P.C. SPARTAN Pro; Wavefunction, I., Ed.; Irvine, CA, 1999.
[11]
Rocha, G.B.; Freire, R.O.; Simas, A.M.; Stewart, J.J.P. RM1: A reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. J. Comput. Chem., 2006, 27(10), 1101-1111.
[http://dx.doi.org/10.1002/jcc.20425] [PMID: 16691568]
[12]
Thomsen, R.; Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking. J. Med. Chem., 2006, 49(11), 3315-3321.
[http://dx.doi.org/10.1021/jm051197e] [PMID: 16722650]
[13]
Guimarães, A.P.; Oliveira, A.A.; da Cunha, E.F.; Ramalho, T.C.; França, T.C.C. Analysis of Bacillus anthracis nucleoside hydrolase via in silico docking with inhibitors and molecular dynamics simulation. J. Mol. Model., 2011, 17(11), 2939-2951.
[http://dx.doi.org/10.1007/s00894-011-0968-9] [PMID: 21318235]
[14]
Lee, H-G.; Kim, M-J.; Park, S-E.; Kim, J-J.; Kim, B.R.; Lee, S-G.; Yoon, Y-J. Phenyl 4,5-dichloro-6-oxopyridazine-1(6h)-carboxylate as carbonyl source: Facile and selective synthesis of carbamates and ureas under mild conditions. Synlett, 2009, 17, 2809-2814.
[15]
Slocombe, R.J.; Hardy, E.E.; Saunders, J.H.; Jenkins, R.L. Phosgene derivatives. The preparation of isocyanates, carbamyl chlorides and cyanuric acid. J. Am. Chem. Soc., 1950, 72(5), 1888-1891.
[http://dx.doi.org/10.1021/ja01161a009]
[16]
Zhao, J.; Li, Z.; Yan, S.; Xu, S.; Wang, M.A.; Fu, B.; Zhang, Z. Pd/C catalyzed carbonylation of azides in the presence of amines. Org. Lett., 2016, 18(8), 1736-1739.
[http://dx.doi.org/10.1021/acs.orglett.6b00381] [PMID: 27015001]
[17]
Chen, J.; Ling, G.; Lu, S. Synthesis of N-Phenyl-N′-pyrimidylurea Derivatives by selenium- or selenium dioxide-catalyzed reductive carbonylation of nitroaromatics. Eur. J. Org. Chem., 2003, 17, 3446-3452.
[http://dx.doi.org/10.1002/ejoc.200300127]
[18]
Bin, L.; Bingdong, L.; Changling, L.; Xiaoli, W. Syntheses and herbicidal activities of pyrimidylureas. Chem. Res. Applic., 1997, 9(1), 49-53.
[19]
Kontoyianni, M.; McClellan, L.M.; Sokol, G.S. Evaluation of docking performance: comparative data on docking algorithms. J. Med. Chem., 2004, 47(3), 558-565.
[http://dx.doi.org/10.1021/jm0302997] [PMID: 14736237]

Rights & Permissions Print Cite
Article Metrics
17
1
© 2024 Bentham Science Publishers | Privacy Policy