Abstract
Background: Thiohydantoins are an important class of heterocyclic compounds in drug discovery since they are related to a wide range of biological properties including antimicrobial activity.
Objective: The objective of this study was to synthesize a series of thiohydantoins derived from Laminoacids and to evaluated their inhibitory effect on the growth of Gram-negative and Grampositive bacteria.
Methods: All title compounds were synthetized by reaction of L-amino acids with thiourea or ammonium thiocyanate. Their antimicrobial activities were evaluated against bacterial strains by broth microdilution assays. The time-kill kinetics, the antibiofilm activity and the cytotoxicity to mammalian cells were determined for the compound that exhibited the best antimicrobial profile (1b).
Results: Eleven thiohydantoins were readily obtained in good yields (52-95%). In general, thiohydantoins were more effective against Gram-positive bacteria. Compound 1b (derived from Lalanine) showed the best antibacterial activity against Staphylococcus epidermis ATCC 12228 and S. aureus BEC 9393 with MIC values of 940 and 1921 µM, respectively. The time-kill kinetics demonstrated time-dependent bactericidal effect in both strains for this derivative. Besides, 1b also exhibited antibacterial activity against biofilms of S. epidermidis ATCC 12228, leading to a 40% reduction in their metabolic activity compared to the untreated control. No cytotoxicity of 1b to mammalian cells was observed at MIC values.
Conclusion: The data reported herein indicate relevant antimicrobial activity of thiohydantoins derived from L-aminoacid, mainly 1b, as potential pharmacophore to guide further chemical modification aiming at the search for new and improved antimicrobial agents.
Keywords: Synthesis, thiohydantoins, acylthioureas, acyl-thiohydantoins, antibacterial activity, antibiofilm activity.
Graphical Abstract
[1]
Wenzel, R.P.; Edmond, M.B. The impact of hospital-acquired bloodstream infections. Emerg. Infect. Dis., 2001, 7(2), 174-177.
[http://dx.doi.org/10.3201/eid0702.010203] [PMID: 11294700]
[http://dx.doi.org/10.3201/eid0702.010203] [PMID: 11294700]
[2]
Health care-associated infections Fact Sheet. http://www.who.int/gpsc/country_work/gpsc_ccisc_fact_sheet_en.pdf [Accessed Oct 18, 2017]
[3]
Klevens, R.M.; Edwards, J.R.; Richards, C.L., Jr; Horan, T.C.; Gaynes, R.P.; Pollock, D.A.; Cardo, D.M. Estimating health care-associated infections and deaths in U.S. hospitals, 2002. Public Health Rep., 2007, 122(2), 160-166.
[http://dx.doi.org/10.1177/003335490712200205] [PMID: 17357358]
[http://dx.doi.org/10.1177/003335490712200205] [PMID: 17357358]
[4]
Ventola, C.L. The antibiotic resistance crisis: Part 1: Causes and threats. P&T, 2015, 40(4), 277-283.
[PMID: 25859123]
[PMID: 25859123]
[5]
Allen, H.K.; Trachsel, J.; Looft, T.; Casey, T.A. Finding alternatives to antibiotics. Ann. N. Y. Acad. Sci., 2014, 1323, 91-100.
[http://dx.doi.org/10.1111/nyas.12468] [PMID: 24953233]
[http://dx.doi.org/10.1111/nyas.12468] [PMID: 24953233]
[6]
Poyraz, S.; Belveren, S.; Ülger, M.; Sahin, E.; Döndas, H.A. Synthesis, characterization, crystal structure and anti-tuberculosis activity of some novel polysubstituted aminocarbothiol/thiohydantoin-pyrrolidine derivatives. Monatsh. Chem., 2017, 148(12), 2173-2182.
[http://dx.doi.org/10.1007/s00706-017-2039-0]
[http://dx.doi.org/10.1007/s00706-017-2039-0]
[7]
Abubshait, S.A. Synthesis, antimicrobial and anticancer activities of some 2-thiohydantoin derivatives. Indian J. Chem., 2017, 56B, 641-648.
[8]
Souza, S.P.; Masteloto, H.G.; Silva, D.S.; Azambuja, J.H.; Braganhol, E.; Ribeiro, J.S.; Lund, R.G.; Cunico, W. Antimicrobial and citoxicity activities of 2-(aryl)-3-(benzo[d][1,3]dioxol-5-yl)thiazolidin-4-ones. Lett. Drug Des. Discov., 2017, 14, 1042-1047.
[http://dx.doi.org/10.2174/1570180814666170106143418]
[http://dx.doi.org/10.2174/1570180814666170106143418]
[9]
Thanusu, J.; Kanagarajan, V.; Gopalakrishnan, M. Synthesis, spectral analysis and in vitro microbiological evaluation of 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones as a new class of antibacterial and antifungal agents. Bioorg. Med. Chem. Lett., 2010, 20(2), 713-717.
[http://dx.doi.org/10.1016/j.bmcl.2009.11.074] [PMID: 20004098]
[http://dx.doi.org/10.1016/j.bmcl.2009.11.074] [PMID: 20004098]
[10]
Wu, F.; Jiang, H.; Zheng, B.; Kogiso, M.; Yao, Y.; Zhou, C.; Li, X.N.; Song, Y. Inhibition of cancer-associated mutant isocitrate dehydrogenases by 2-thiohydantoin compounds. J. Med. Chem., 2015, 58(17), 6899-6908.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00684] [PMID: 26280302]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00684] [PMID: 26280302]
[11]
Raj, R.; Mehra, V.; Gut, J.; Rosenthal, P.J.; Wicht, K.J.; Egan, T.J.; Hopper, M.; Wrischnik, L.A.; Land, K.M.; Kumar, V. Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity. Eur. J. Med. Chem., 2014, 84, 425-432.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.048] [PMID: 25038484]
[http://dx.doi.org/10.1016/j.ejmech.2014.07.048] [PMID: 25038484]
[12]
Suzen, S.; Buyukbingol, E. Evaluation of anti-HIV activity of 5-(2-phenyl-3′-indolal)-2-thiohydantoin. Farmaco, 1998, 53(7), 525-527.
[http://dx.doi.org/10.1016/S0014-827X(98)00053-6] [PMID: 9836465]
[http://dx.doi.org/10.1016/S0014-827X(98)00053-6] [PMID: 9836465]
[13]
Porwal, S.; Chauhan, S.S.; Chauhan, P.M.S.; Shakya, N.; Verma, A.; Gupta, S. Discovery of novel antileishmanial agents in an attempt to synthesize pentamidine-aplysinopsin hybrid molecule. J. Med. Chem., 2009, 52(19), 5793-5802.
[http://dx.doi.org/10.1021/jm900564x] [PMID: 19743860]
[http://dx.doi.org/10.1021/jm900564x] [PMID: 19743860]
[14]
Karali, N.; Gürsoy, A.; Terzioglu, N.; Ozkirimli, S.; Ozer, H.; Ekinci, A.C. Synthesis and preliminary CNS depressant activity evaluation of new 3-[(3-substituted-5-methyl-4-thiazolidinon-2-ylidene)hydrazono]-1H-2- indolinones and 3-[(2-thioxo-3-substituted-4,5-imidazolidinedion-1-yl) imino]-1H-2-indolinones. Arch. Pharm. (Weinheim), 1998, 331(7-8), 254-258.
[http://dx.doi.org/10.1002/(SICI)1521-4184(199807)331:7/8<254:AID-ARDP254>3.0.CO;2-R] [PMID: 9747182]
[http://dx.doi.org/10.1002/(SICI)1521-4184(199807)331:7/8<254:AID-ARDP254>3.0.CO;2-R] [PMID: 9747182]
[15]
S.; Salhi, L.; Belkebir, A.; Ait-Yahia, O.; Boudjlida, A.; Bouguerra-Aouichat, S.; Nedjar-Kolli, B. Antioxidant and anti tumoral activities of hydrazylpyrrolidine 2,5 dione substituted and 2-thioxo imidazolidine 4-one. Int. J. Pharm. Chem. Biol. Sci., 2014, 4(3), 447-452.
[16]
Buchynskyy, A.; Gillespie, J.R.; Herbst, Z.M.; Ranade, R.M.; Buckner, F.S.; Gelb, M.H. 1-Benzyl-3-aryl-2-thiohydantoin derivatives as new anti-Trypanosoma brucei agents: SAR and in vivo Efficacy. ACS Med. Chem. Lett., 2017, 8(8), 886-891.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00230] [PMID: 28835807]
[http://dx.doi.org/10.1021/acsmedchemlett.7b00230] [PMID: 28835807]
[17]
Tompkins, J.E. 5,5-Diaryl-2-thiohydantoins and 5,5-diaryl-N3-substituted-2-thiohydantoins as potential hypolipidemic agents. J. Med. Chem., 1986, 29(5), 855-859.
[http://dx.doi.org/10.1021/jm00155a042] [PMID: 2939244]
[http://dx.doi.org/10.1021/jm00155a042] [PMID: 2939244]
[18]
al-Obaid, A.M.; el-Subbagh, H.I.; Khodair, A.I.; Elmazar, M.M.A. 5-substituted-2-thiohydantoin analogs as a novel class of antitumor agents. Anticancer Drugs, 1996, 7(8), 873-880.
[http://dx.doi.org/10.1097/00001813-199611000-00009] [PMID: 8991192]
[http://dx.doi.org/10.1097/00001813-199611000-00009] [PMID: 8991192]
[19]
Marx, J.V.; Richert, D.A.; Westerfeld, W.W. Peripheral inhibition of thyroxine by thiohydantoins derived from amino acids. J. Med. Chem., 1970, 13(6), 1179-1181.
[http://dx.doi.org/10.1021/jm00300a036] [PMID: 5479861]
[http://dx.doi.org/10.1021/jm00300a036] [PMID: 5479861]
[20]
Marton, J.; Enisz, J.; Hosztafi, S.; Timar, T. Preparation and fungicidal activity of 5-substituted hydantoins and their 2-thio analogs. J. Agric. Food Chem., 1993, 41, 148-152.
[http://dx.doi.org/10.1021/jf00025a031]
[http://dx.doi.org/10.1021/jf00025a031]
[21]
LeTiran, A.; Stables, J.P.; Kohn, H. Functionalized amino acid anticonvulsants: Synthesis and pharmacological evaluation of conformationally restricted analogues. Bioorg. Med. Chem., 2001, 9(10), 2693-2708.
[http://dx.doi.org/10.1016/S0968-0896(01)00204-8] [PMID: 11557357]
[http://dx.doi.org/10.1016/S0968-0896(01)00204-8] [PMID: 11557357]
[22]
Cheymol, J.; Chabrier, P.; Gay, Y. Antithyroid action and molecular structure. I. A study of thiohydantoins and their methyl esters. Arch. Int. Pharmacodyn. Ther., 1951, 87(3), 321-333.
[PMID: 14895194]
[PMID: 14895194]
[23]
Cunha, S.; Macedo, F.C., Jr; Costa, G.A.N.; Rodrigues, M.T., Jr; Verde, R.B.V.; Neta, L.C.S.; Vencato, I.; Lariucci, C.; Sá, F.P. Antimicrobial activity and structural study of disubstituted thiourea derivatives. Monatsh. Chem., 2007, 138, 511-516.
[http://dx.doi.org/10.1007/s00706-007-0600-y]
[http://dx.doi.org/10.1007/s00706-007-0600-y]
[24]
El Hady, H.A. Synthesis and antimicrobial activity of some new thiohydantoin and thiazole derivatives. Pharma Chem., 2012, 4(6), 2202-2207.
[25]
Kachhadia, V.V.; Patel, M.R.; Joshi, H.S. Heterocyclic systems containing S/N regioselective nucleophilic competition: Facile synthesis, antitubercular and antimicrobial activivty of thiohydantoins and iminothiazolidinones containing the benzo [b]thiophene moiety. J. Serb. Chem. Soc., 2005, 70(2), 153-161.
[http://dx.doi.org/10.2298/JSC0502153K]
[http://dx.doi.org/10.2298/JSC0502153K]
[26]
Mohamed, N.A.; Abd El-Ghany, N.A. Preparation and antimicrobial activity of some carboxymethyl chitosan acyl thiourea derivatives. Int. J. Biol. Macromol., 2012, 50(5), 1280-1285.
[http://dx.doi.org/10.1016/j.ijbiomac.2012.03.011] [PMID: 22469914]
[http://dx.doi.org/10.1016/j.ijbiomac.2012.03.011] [PMID: 22469914]
[27]
Diţu, L.M.; Mihăescu, G.; Chifiriuc, C.; Bleotu, C.; Morusciag, L.; Niţulescu, G.M.; Missir, A. In vitro assessment of the antimicrobial activity of new N-acyl-thiourea derivatives. Roum. Arch. Microbiol. Immunol., 2010, 69(1), 41-47.
[PMID: 21053783]
[PMID: 21053783]
[28]
Cromwell, L.D.; Stark, G.R. Determination of the carboxyl termini of proteins with ammonium thiocyanate and acetic anhydride, with direct identification of the thiohydantoins. Biochemistry, 1969, 8(12), 4735-4740.
[http://dx.doi.org/10.1021/bi00840a012] [PMID: 4904040]
[http://dx.doi.org/10.1021/bi00840a012] [PMID: 4904040]
[29]
Wang, Z.D.; Sheikh, S.O.; Zhang, Y. A simple synthesis of 2-thiohydantoins. Molecules, 2006, 11(10), 739-750.
[http://dx.doi.org/10.3390/11100739] [PMID: 17971750]
[http://dx.doi.org/10.3390/11100739] [PMID: 17971750]
[30]
Elmore, D.T.; Ogle, J.R.; Toseland, P.A. Degradative studies on peptides and proteins. Part III. Synthesis of some 2-thiohydantoins as reference compounds. J. Chem. Soc., 1956, 192-196.
[http://dx.doi.org/10.1039/jr9560000192]
[http://dx.doi.org/10.1039/jr9560000192]
[31]
Reyes, S.; Burgess, K. On formation of thiohydantoins from amino acids under acylation conditions. J. Org. Chem., 2006, 71(6), 2507-2509.
[http://dx.doi.org/10.1021/jo052576i] [PMID: 16526805]
[http://dx.doi.org/10.1021/jo052576i] [PMID: 16526805]
[32]
Duggan, B.M.; Laslett, R.L.; Wilshire, J.F.K. Studies in thiohydantoin chemistry. I Some aspects of the schlack-kumpf reaction. Aust. J. Chem., 1996, 49, 541-550.
[http://dx.doi.org/10.1071/CH9960541]
[http://dx.doi.org/10.1071/CH9960541]
[33]
Gosling, S.; Rollin, P.; Tatibouët, A. Thiohydantoins: Selective N- and S-functionalization for liebeskind-srogl reaction study. Synthesis, 2011, 22, 3649-3660.
[34]
Elmore, D.T.; Toseland, P.A. Degradative studies on peptides and proteins. Part I. A new method of stepwise degradation of peptides from the end bearing a free amino-group, employing N-Acyldithiocarbamates. J. Chem. Soc., 1954, 4533-4537.
[http://dx.doi.org/10.1039/jr9540004533]
[http://dx.doi.org/10.1039/jr9540004533]
[35]
M26-A. Clinical and laboratory standards institute: Performance standards for antimicrobial susceptibility testing. In: Twenty-Fourth Informational Supplement, Document M100, 27th Ed.; Clinical and Laboratory Standards Institute, Wayne, PA: CLSI, 2017.
[36]
Clinical and laboratory standards institute. In: Methods for determining bactericidal activity of antimicrobial agents: Approved guideline; Document M26-A, Clinical and Laboratory Standards Institute, Wayne, PA: CLSI, 1999.
[37]
Stepanović, S.; Vuković, D.; Hola, V.; Di Bonaventura, G.; Djukić, S.; Cirković, I.; Ruzicka, F. Quantification of biofilm in microtiter plates: overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci. APMIS, 2007, 115(8), 891-899.
[http://dx.doi.org/10.1111/j.1600-0463.2007.apm_630.x] [PMID: 17696944]
[http://dx.doi.org/10.1111/j.1600-0463.2007.apm_630.x] [PMID: 17696944]
[38]
Zago, C.E.; Silva, S.; Sanitá, P.V.; Barbugli, P.A.; Dias, C.M.; Lordello, V.B.; Vergani, C.E. Dynamics of biofilm formation and the interaction between Candida albicans and methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA). PLoS One, 2015, 10(4)e0123206
[http://dx.doi.org/10.1371/journal.pone.0123206] [PMID: 25875834]
[http://dx.doi.org/10.1371/journal.pone.0123206] [PMID: 25875834]
[39]
Johnson, T.B.; Chernoff, L.H. Hydantoins: Synthesis of 5-Thiohydantoins. J. Am. Chem. Soc., 1912, 35, 1208-1213.
[http://dx.doi.org/10.1021/ja02210a011]
[http://dx.doi.org/10.1021/ja02210a011]
[40]
Johnson, T.B. Hydantoins: The action of potassium thiocyanate on alanine. J. Biol. Chem., 1912, 11(2), 97-101.
[41]
Arias, C.A.; Reyes, J.; Carvajal, L.P.; Rincon, S.; Diaz, L.; Panesso, D.; Ibarra, G.; Rios, R.; Munita, J.M.; Salles, M.J.; Alvarez-Moreno, C.; Labarca, J.; Garcia, C.; Luna, C.M.; Mejia-Villatoro, C.; Zurita, J.; Guzman-Blanco, M.; Rodriguez-Noriega, E.; Narechania, A.; Rojas, L.J.; Planet, P.J.; Weinstock, G.M.; Gotuzzo, E.; Seas, C. A prospective cohort multicenter study of molecular epidemiology and phylogenomics of Staphylococcus aureus bacteremia in nine Latin American countries. Antimicrob. Agents Chemother., 2017, 61(10), 1-12.
[http://dx.doi.org/10.1128/AAC.00816-17] [PMID: 28760895]
[http://dx.doi.org/10.1128/AAC.00816-17] [PMID: 28760895]
[42]
Hiramatsu, K.; Katayama, Y.; Matsuo, M.; Sasaki, T.; Morimoto, Y.; Sekiguchi, A.; Baba, T. Multi-drug-resistant Staphylococcus aureus and future chemotherapy. J. Infect. Chemother., 2014, 20(10), 593-601.
[http://dx.doi.org/10.1016/j.jiac.2014.08.001] [PMID: 25172776]
[http://dx.doi.org/10.1016/j.jiac.2014.08.001] [PMID: 25172776]
[43]
Oliveira, W.F.; Silva, P.M.S.; Silva, R.C.S.; Silva, G.M.M.; Machado, G.; Coelho, L.C.B.B.; Correia, M.T.S. Staphylococcus aureus and Staphylococcus epidermidis infections on implants. J. Hosp. Infect., 2018, 98(2), 111-117.
[http://dx.doi.org/10.1016/j.jhin.2017.11.008] [PMID: 29175074]
[http://dx.doi.org/10.1016/j.jhin.2017.11.008] [PMID: 29175074]
[44]
Donlan, R.M.; Costerton, J.W. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin. Microbiol. Rev., 2002, 15(2), 167-193.
[http://dx.doi.org/10.1128/CMR.15.2.167-193.2002] [PMID: 11932229]
[http://dx.doi.org/10.1128/CMR.15.2.167-193.2002] [PMID: 11932229]
Article Metrics
23
1