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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Benzoylthioureas: Design, Synthesis and Antimycobacterial Evaluation

Author(s): Tiago O. Brito, Lethícia O. Abreu, Karen M. Gomes, Maria C.S. Lourenço, Patricia M.L. Pereira, Sueli F. Yamada-Ogatta, Ângelo de Fátima, Cesar A. Tisher, Fernando Macedo Jr and Marcelle L.F. Bispo*

Volume 16, Issue 1, 2020

Page: [93 - 103] Pages: 11

DOI: 10.2174/1573406415666181208110753

Price: $65

Abstract

Background: New drugs and strategies to treat tuberculosis (TB) are urgently needed. In this context, thiourea derivatives have a wide range of biological activities, including anti-TB. This fact can be illustrated with the structure of isoxyl, an old anti-TB drug, which has a thiourea as a pharmacophore group.

Objective: The aim of this study is to describe the synthesis and the antimycobacterial activity of fifty-nine benzoylthioureas derivatives.

Methods: Benzoylthiourea derivatives have been synthesized and evaluated for their activity against Mycobacterium tuberculosis using the MABA assay. After that, a structure-activity relationship study of this series of compounds has been performed.

Results and Discussion: Nineteen compounds exhibited antimycobacterial activity between 423.1 and 9.6 μM. In general, we observed that the presence of bromine, chlorine and t-Bu group at the para-position in benzene ring plays an important role in the antitubercular activity of Series A. These substituents were fixed at this position in benzene ring and other groups such as Cl, Br, NO2 and OMe were introduced in the benzoyl ring, leading to the derivatives of Series B. In general, Series B was less cytotoxic than Series A, which indicates that the presence of a substituent at benzoyl ring contributes to an improvement in both antimycobacterial activity and toxicity profiles.

Conclusion: Compound 4c could be considered a good prototype to be submitted to further structural modifications in the search for new anti-TB drugs, since it is 1.8 times more active than the first line anti-TB drug ethambutol and 0.65 times less active than isoxyl.

Keywords: Antimycobacterial activity, tuberculosis, thioureas, benzoylthioureas, structure-activity relationship, drugs.

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[1]
World Health Organization; Global Tuberculosis Report 2016; Geneva,. , 2016.
[2]
World Health Organization; Multidrug-Resistant Tuberculosis (MDR-TB) 2016 Update; ; Geneva . , 2016.
[3]
World Health Organization; Drug-resistant TB: XDR-TB FAQ., Available at: . http://www.who.int/tb/areas-of-work/drug-resistant-tb/xdr-tb-faq/en/
[4]
Mdluli, K.; Kaneko, T.; Upton, A. The tuberculosis drug discovery and development pipeline and emerging drug targets. Cold Spring Harb. Perspect. Med., 2015, 5(6)a021154
[http://dx.doi.org/10.1101/cshperspect.a021154] [PMID: 25635061]
[5]
Egan, T.J.; Koch, K.R.; Swan, P.L.; Clarkson, C.; Van Schalkwyk, D.A.; Smith, P.J. In vitro antimalarial activity of a series of cationic 2,2′-bipyridyl- and 1,10-phenanthrolineplatinum(II) benzoylthio-urea complexes. J. Med. Chem., 2004, 47(11), 2926-2934.
[http://dx.doi.org/10.1021/jm031132g] [PMID: 15139771]
[6]
Mahajan, A.; Yeh, S.; Nell, M.; van Rensburg, C.E.J.; Chibale, K. Synthesis of new 7-chloroquinolinyl thioureas and their biological investigation as potential antimalarial and anticancer agents. Bioorg. Med. Chem. Lett., 2007, 17(20), 5683-5685.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.049] [PMID: 17768052]
[7]
Loev, B.; Bender, P.E.; Bowman, H.; Helt, A.; McLean, R.; Jen, T. Amidines. 3. Thioureas possessing antihypertensive activity. J. Med. Chem., 1972, 15(10), 1024-1027.
[http://dx.doi.org/10.1021/jm00280a007] [PMID: 5069768]
[8]
Phuong, T.; Khac-Minh, T.; Van Ha, N.T.; Ngoc Phuong, H.T. Synthesis and antifungal activities of phenylenedithioureas. Bioorg. Med. Chem. Lett., 2004, 14(3), 653-656.
[http://dx.doi.org/10.1016/j.bmcl.2003.11.044] [PMID: 14741262]
[9]
Cunha, S.; Macedo, F.C.; Costa, G.A.N.; Rodrigues, M.T.; Verde, R.B.V.; de Souza Neta, L.C.; Vencato, I.; Lariucci, C.; Sá, F.P. Antimicrobial activity and structural study of disubstituted thiourea derivatives. Monatshefte für Chemie - Chem. Mon., 2007, 138, 511-516.
[10]
Zhao, M-M.; Dong, X-Y.; Li, G.; Yang, Y-H.; Zhang, Y-J.; Yang, X-Q. Antituberculosis and antifungal activities of synthesized benzoylthiourea derivatives. Asian J. Chem., 2013, 25, 7548-7550.
[http://dx.doi.org/10.14233/ajchem.2013.15157]
[11]
Phetsuksiri, B.; Baulard, A.R.; Cooper, A.M.; Minnikin, D.E.; Douglas, J.D.; Besra, G.S.; Brennan, P.J. Antimycobacterial activities of isoxyl and new derivatives through the inhibition of mycolic acid synthesis. Antimicrob. Agents Chemother., 1999, 43(5), 1042-1051.
[http://dx.doi.org/10.1128/AAC.43.5.1042] [PMID: 10223912]
[12]
Kampelmann, F. Results of monotherapy with Isoxyl in untreated pulmonary tuberculosis cases of different difficulties and Isoxyl in routine-therapy. Antibiot. Chemother., 1970, 16, 96-104.
[http://dx.doi.org/10.1159/000386808] [PMID: 5535617]
[13]
Urbancik, B. A clinical trial of thiocarlide (4-4′ diisoamyloxythiocarbanilide). Tubercle, 1966, 47(3), 283-288.
[http://dx.doi.org/10.1016/S0041-3879(66)80007-7] [PMID: 5339425]
[14]
Tousek, J. On the clinical effectiveness of Isoxyl. Antibiot. Chemother., 1970, 16, 149-155.
[http://dx.doi.org/10.1159/000386816] [PMID: 4943580]
[15]
Wang, C.; Hickey, A.J. Isoxyl aerosols for tuberculosis treatment: preparation and characterization of particles. AAPS PharmSciTech, 2010, 11(2), 538-549.
[http://dx.doi.org/10.1208/s12249-010-9415-y] [PMID: 20339959]
[16]
Emerson, P.A.; Lacey, B.W.; Breach, M.R. A bacteriological study of thiocarlide monotherapy. Tubercle, 1969, 50(3), 273-279.
[http://dx.doi.org/10.1016/0041-3879(69)90052-X] [PMID: 5388381]
[17]
Brito, T.O.; Souza, A.X.; Mota, Y.C.C.; Morais, V.S.S.; de Souza, L.T.; de Fatima, A.; Macedo, F.; Modolo, L.V. Design, syntheses and evaluation of benzoylthioureas as urease inhibitors of agricultural interest. RSC Advances, 2015, 5, 44507-44515.
[http://dx.doi.org/10.1039/C5RA07886E]
[18]
Otazo-Sánchez, E.; Pérez-Marín, L.; Estévez-Hernández, O.; Rojas-Lima, S.; Alonso-Chamarro, J. Aroylthioureas: New organic ionophores for heavy-metal ion selective electrodes. J. Chem. Soc., Perkin Trans. 2, 2001, 2211.
[http://dx.doi.org/10.1039/b102029n]
[19]
Franzblau, S.G.; Witzig, R.S.; McLaughlin, J.C.; Torres, P.; Madico, G.; Hernandez, A.; Degnan, M.T.; Cook, M.B.; Quenzer, V.K.; Ferguson, R.M.; Gilman, R.H. Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay. J. Clin. Microbiol., 1998, 36(2), 362-366.
[PMID: 9466742]
[20]
Reis, R.S.; Neves, I., Jr; Lourenço, S.L.S.; Fonseca, L.S.; Lourenço, M.C.S. Comparison of flow cytometric and Alamar Blue tests with the proportional method for testing susceptibility of Mycobacterium tuberculosis to rifampin and isoniazid. J. Clin. Microbiol., 2004, 42(5), 2247-2248.
[http://dx.doi.org/10.1128/JCM.42.5.2247-2248.2004] [PMID: 15131202]
[21]
Vanitha, J.D.; Paramasivan, C.N. Evaluation of microplate Alamar blue assay for drug susceptibility testing of Mycobacterium avium complex isolates. Diagn. Microbiol. Infect. Dis., 2004, 49(3), 179-182.
[http://dx.doi.org/10.1016/j.diagmicrobio.2004.04.003] [PMID: 15246507]
[22]
Phetsuksiri, B.; Jackson, M.; Scherman, H.; McNeil, M.; Besra, G.S.; Baulard, A.R.; Slayden, R.A.; DeBarber, A.E.; Barry, C.E., III; Baird, M.S.; Crick, D.C.; Brennan, P.J. Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis. J. Biol. Chem., 2003, 278(52), 53123-53130.
[http://dx.doi.org/10.1074/jbc.M311209200] [PMID: 14559907]
[23]
Kubinyi, H. Chemical similarity and biological activities. J. Braz. Chem. Soc., 2002, 13, 717-726.
[http://dx.doi.org/10.1590/S0103-50532002000600002]
[24]
Carvalho, M.V.; Penido, C.; Siani, A.C.; Valente, L.M.M.; Henriques, M.G.M.O. Investigations on the anti-inflammatory and anti-allergic activities of the leaves of Uncaria guianensis (Aublet) J. F. Gmelin. Inflammopharmacology, 2006, 14(1-2), 48-56.
[http://dx.doi.org/10.1007/s10787-006-1509-5] [PMID: 16835713]
[25]
Souza, M.C.; Siani, A.C.; Ramos, M.F.S.; Menezes-de-Lima, O.J.; Henriques, M.G.M.O. Evaluation of anti-inflammatory activity of essential oils from two Asteraceae species. Pharmazie, 2003, 58(8), 582-586.
[PMID: 12967039]
[26]
Chung, M.C.; Bosquesi, P.L.; dos Santos, J.L. A prodrug approach to improve the physico-chemical properties and decrease the genotoxicity of nitro compounds. Curr. Pharm. Des., 2011, 17(32), 3515-3526.
[http://dx.doi.org/10.2174/138161211798194512] [PMID: 22074424]

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