A Comprehensive Review: Bio-Potential of Barbituric Acid and its Analogues

Nusrat       Shafiq; Uzma       Arshad; Gul       Zarren; Shagufta       Parveen; Irum       Javed; Aisha       Ashraf
Abstract

In our present work, we emphasized on the potential of barbituric acid (1) derivatives as drugs like anti-bacterial, hypnotic, sedative, anti-microbial and antifungal agents. As naturally occurring, barbituric acid (1) is inactive but in the derivative form, it has a large number of medicinal uses and nowadays, it has a great demand in the pharmaceutical industry. Barbituric acid has a wide range of applications in the synthesis of a diverse class of compounds like heterocyclic, carbocyclic, synthetic alkaloids, and due to its broad-spectrum applications, barbituric acid acquired the position of building blocks in synthetic chemistry. Through the history of humanity, a number of bioactive agents have been applied to cure the disease related to hypnotics and sedatives, while the exact efficacy of these agents was found to be limited. Till now, review articles on barbituric acid only express their specific aspect but in present review article, all aspects are discussed in detail to provide a platform to readers and researchers so that they could obtain all information and background knowledge from a single point.
Keywords: Anti-microbial, anti-fungal, barbituric acid derivatives, hypnotic, luminal, multi-component reactions, phenobarbital sedative.
Graphical Abstract

[1] 
Dodia, J.; Dangar, V.; Shah, V. Synthesis, characterization and antimicrobial activity of some new barbitone derivatives. World J. Pharma. Res.,  2017, 6(17), 749-754.
[2] 
Ernst, J. B.; F. Clark, G.; Grundmann, O. The physicochemical and pharmacokinetic relationships of barbiturates-from the past to the future. Curr. Pharm. Des.,  2015, 21(25), 3681-3691.
[http://dx.doi.org/10.2174/1381612821666150331131009] [PMID:  25824249] 
[3] 
Barakat, A.; Al-Majid, A.M.; Soliman, S.M.; Islam, M.S.; Ghawas, H.M.; Yousuf, S.; Choudhary, M.I.; Wadood, A. Monoalkylated barbiturate derivatives: X-ray crystal structure, theoretical studies, and biological activities. J. Mol. Struct.,  2017, 1141, 624-633.
[http://dx.doi.org/10.1016/j.molstruc.2017.04.017] 
[4] 
Mishra, S.; Singh, P. Hybrid molecules: The privileged scaffolds for various pharmaceuticals. Eur. J. Med. Chem.,  2016, 124, 500-536.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.039] [PMID:  27598238] 
[5] 
Kallman, M.J. Hypnotic activity. In: Drug Discovery and Evaluation: Pharmacological Assays; Hock, F.J., Ed.; , 2016; pp. 1307-1315.
[http://dx.doi.org/10.1007/978-3-319-05392-9_29] 
[6] 
Hossain, M.F.; Talukder, B.; Rana, M.N.; Tasnim, R.; Nipun, T.S.; Uddin, S.M.; Hossen, S.M. In vivo sedative activity of methanolic extract of Stericulia villosa Roxb. leaves. BMC Complement. Altern. Med.,  2016, 16(1), 398.
[http://dx.doi.org/10.1186/s12906-016-1374-8] [PMID:  27769218] 
[7] 
Suddock, J.T.; Cain, M.D. Toxicity, Barbiturate. StatPearls. Internet; Stat- Pearls Publishing, 2018. 
[8] 
Ellens, N.R.; Figueroa, B.E.; Clark, J.C. The use of barbiturate-induced coma during cerebrovascular neurosurgery procedures: a review of the literature. Brain Circ.,  2015, 1(2), 140.
[http://dx.doi.org/10.4103/2394-8108.172887] 
[9] 
McGrane, T.J.; McEvoy, M.D.; Reves, J. Intravenous Sedatives and Anesthetics. In: Geriatric Anesthesiology; Springer, 2018; pp. 255-281.
[http://dx.doi.org/10.1007/978-3-319-66878-9_17] 
[10] 
Chowdhury, L.D.; Singh, O.P. Hypnotics and Sedatives In: Psychiatric Drug
Handbook; , 2018; pp. 9-18.
[11] 
Santos, C.; Olmedo, R.; Kim, J. Sedative-hypnotic drug withdrawal syndrome: recognition and treatment [digest]. Emerg. Med. Prac.,  2017, 19(3 Suppl Points & Pearls), S1-S2.
[12] 
Mahernia, S.; Sharifi, N.; Hassanzadeh, M.; Rahimi, N.; Pourshadi, N.; Amanlou, A.; Dehpour, A.R.; Amanlou, M. Benzylidene barbituric acid derivatives shown anticonvulsant activity on pentylenetetrazole-induced seizures in mice: involvement of nitric oxide pathway. Pharm. Sci.,  2018, 24(4), 250.
[http://dx.doi.org/10.15171/PS.2018.37] 
[13] 
Walsh, S.J.; Katz, K.D. Barbiturates. In: Critical Care Toxicology; Springer, 2016; pp. 1-10.
[14] 
Ray, R.K.; Upadhyay, S.; Limaye, S.N.; Yadav, S. Association of barbiturates in biological activities as a toxicological agent. Ind. J. Forens. Med. Toxic.,  2018, 12(2), 165-170.
[http://dx.doi.org/10.5958/0973-9130.2018.00096.8] 
[15] 
McGinn, K.A.; Bishop, L.; Sarwal, A. Use of ketamine in barbiturate coma for status epilepticus. Clin. Neuropharmacol.,  2016, 39(1), 62-65.
[http://dx.doi.org/10.1097/WNF.0000000000000128] [PMID:  26757317] 
[16] 
Millichapf, J.G.H. Anticonvulsant drugs. In: The Nervous System; Central Nervous System Drugs, 2016; p. 97.
[17] 
Allgulander, C. Barbiturates In: Encyclopedia of Psychopharmacology; ,  2015; pp. 248-254.
[18] 
Neumann, D. The Design and Synthesis of Novel Barbiturates of Pharmaceutical Interest., 2004.
[19] 
López-Muñoz, F.; Ucha-Udabe, R.; Alamo, C. The history of barbiturates a century after their clinical introduction. Neuropsychiatr. Dis. Treat.,  2005, 1(4), 329-343.
[PMID:  18568113] 
[20] 
Kim, S.H.; Pudzianowski, A.T.; Leavitt, K.J.; Barbosa, J.; McDonnell, P.A.; Metzler, W.J.; Rankin, B.M.; Liu, R.; Vaccaro, W.; Pitts, W. Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13). Bioorg. Med. Chem. Lett.,  2005, 15(4), 1101-1106.
[http://dx.doi.org/10.1016/j.bmcl.2004.12.016] [PMID:  15686921] 
[21] 
Daniewski, A.R.; Liu, W.; Okabe, M. An improved synthesis of the selective matrix metalloproteinase inhibitor, Ro 28-2653. Org. Process Res. Dev.,  2004, 8, 411-414.
[http://dx.doi.org/10.1021/op049965j] 
[22] 
Suzuki, H.; Kneller, M.B.; Rock, D.A.; Jones, J.P.; Trager, W.F.; Rettie, A.E. Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors. Arch. Biochem. Biophys.,  2004, 429(1), 1-15.
[http://dx.doi.org/10.1016/j.abb.2004.05.015] [PMID:  15288804] 
[23] 
Haldar, M.K.; Scott, M.D.; Sule, N.; Srivastava, D.K.; Mallik, S. Synthesis of barbiturate-based methionine aminopeptidase-1 inhibitors. Bioorg. Med. Chem. Lett.,  2008, 18(7), 2373-2376.
[http://dx.doi.org/10.1016/j.bmcl.2008.02.066] [PMID:  18343108] 
[24] 
Uhlmann, C.; Fröscher, W. Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: results from a questionnaire study. CNS Neurosci. Ther.,  2009, 15(1), 24-31.
[http://dx.doi.org/10.1111/j.1755-5949.2008.00073.x] [PMID:  19228177] 
[25] 
Archana, S.; Srivastava, V.K.; Kumar, A. Synthesis of some newer derivatives of substituted quinazolinonyl-2-oxo/thiobarbituric acid as potent anticonvulsant agents. Bioorg. Med. Chem.,  2004, 12(5), 1257-1264.
[http://dx.doi.org/10.1016/j.bmc.2003.08.035] [PMID:  14980637] 
[26] 
Agarwal, A.; Lata, S.; Saxena, K.K.; Srivastava, V.K.; Kumar, A. Synthesis and anticonvulsant activity of some potential thiazolidinonyl 2-oxo/thiobarbituric acids. Eur. J. Med. Chem.,  2006, 41(10), 1223-1229.
[http://dx.doi.org/10.1016/j.ejmech.2006.03.029] [PMID:  16919852] 
[27] 
Maquoi, E.; Sounni, N.E.; Devy, L.; Olivier, F.; Frankenne, F.; Krell, H.W.; Grams, F.; Foidart, J.M.; Noël, A. Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor. Clin. Cancer Res.,  2004, 10(12 Pt 1), 4038-4047.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-0125] [PMID:  15217936] 
[28] 
Jursic, B.S.; Doulle, F.; Stevens, E.D. Preparation of 5-diaminomethylenebarbiturates by barbituric acid addition to carbodiimides. Tetrahedron,  2003, 59(19), 3427-3432.
[http://dx.doi.org/10.1016/S0040-4020(03)00489-7] 
[29] 
Penthala, N.R.; Yerramreddy, T.R.; Crooks, P.A. Synthesis and in vitro screening of novel N-benzyl aplysinopsin analogs as potential anticancer agents. Bioorg. Med. Chem. Lett.,  2011, 21(5), 1411-1413.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.020] [PMID:  21295476] 
[30] 
Singh, P.; Kaur, M.; Verma, P. Design, synthesis and anticancer activities of hybrids of indole and barbituric acids--identification of highly promising leads. Bioorg. Med. Chem. Lett.,  2009, 19(11), 3054-3058.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.014] [PMID:  19398334] 
[31] 
Morgan, L.R.; Jursic, B.S.; Hooper, C.L.; Neumann, D.M.; Thangaraj, K.; LeBlanc, B. Anticancer activity for 4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) analogues and their abilities to interact with lymphoendothelial cell surface markers. Bioorg. Med. Chem. Lett.,  2002, 12(23), 3407-3411.
[http://dx.doi.org/10.1016/S0960-894X(02)00725-4] [PMID:  12419372] 
[32] 
Brouwer, W.G.; Felauerand, E.E.; Bell, A.R. US Patent 779,982. In: Chem.
Abstr; , 1991. 
[33] 
Rajamaki, S.; Innitzer, A.; Falciani, C.; Tintori, C.; Christ, F.; Witvrouw, M.; Debyser, Z.; Massa, S.; Botta, M. Exploration of novel thiobarbituric acid-, rhodanine- and thiohydantoin-based HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett.,  2009, 19(13), 3615-3618.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.132] [PMID:  19447621] 
[34] 
Guillén Sans, R.; Guzmán Chozas, M. Historical aspects and applications of barbituric acid derivatives. A review. Pharmazie,  1988, 43(12), 827-829.
[PMID:  3073393] 
[35] 
Ziarani, G.M.; Aleali, F.; Lashgari, N. Recent applications of barbituric acid in multicomponent reactions. RSC Advances,  2016, 6(56), 50895-50922.
[http://dx.doi.org/10.1039/C6RA09874F] 
[36] 
Vieira, A.A.; Gomes, N.M.; Matheus, M.E.; Fernandes, P.D.; Figueroa-Villar, J.D. Synthesis and in vivo evaluation of 5-chloro-5-benzobarbiturates as new central nervous system depressants. J. Braz. Chem. Soc.,  2011, 22(2), 364-371.
[http://dx.doi.org/10.1590/S0103-50532011000200024] 
[37] 
Barakat, A.; Soliman, S.M.; Elshaier, Y.A.; Ali, M.; Al-Majid, A.M.; Ghabbour, H.A. Molecular structure and spectroscopic investigations combined with hypoglycemic/anticancer and docking studies of a new barbituric acid derivative. J. Mol. Struct.,  2017, 1134, 99-111.
[http://dx.doi.org/10.1016/j.molstruc.2016.12.072] 
[38] 
Jeong, Y-C.; Moloney, M.G. Antibacterial barbituric acid analogues inspired from natural 3-acyltetramic acids; synthesis, tautomerism and structure and physicochemical property-antibacterial activity relationships. Molecules,  2015, 20(3), 3582-3627.
[http://dx.doi.org/10.3390/molecules20033582] [PMID:  25710842] 
[39] 
Ambrożak, A.; Steinebach, C.; Gardner, E.R.; Beedie, S.L.; Schnakenburg, G.; Figg, W.D.; Gütschow, M. Synthesis and antiangiogenic properties of tetrafluorophthalimido and tetrafluorobenzamido barbituric acids. ChemMedChem,  2016, 11(23), 2621-2629.
[http://dx.doi.org/10.1002/cmdc.201600496] [PMID:  27805767] 
[40] 
Mohammadi Ziarani, G.; Asadi, S.; Faramarzi, S.; Amanlou, M. Green synthesis and urease inhibitory activity of spiro-pyrimidinethiones/spiro-pyrimidinones-barbituric acid derivatives. Iran. J. Pharm. Res.,  2015, 14(4), 1105-1114.
[PMID:  26664377] 
[41] 
Shukla, S.; Bishnoi, A.; Devi, P.; Kumar, S.; Srivastava, A.; Srivastava, K.; Fatma, S. Synthesis, characterization and in vitro antibacterial evaluation of barbituric acid derivatives. Russ. J. Org. Chem.,  2019, 55(6), 860-865.
[http://dx.doi.org/10.1134/S1070428019060174] 
[42] 
Fahad, M.M.; Zimam, E.H.; Mohamad, M.J. Synthesis and antimicrobial activity of some new barbituric acid derivatives containing thiazole moiety from sulfadiazine. Nano Biomed. Eng.,  2019, 11(2), 124-137.
[http://dx.doi.org/10.5101/nbe.v11i2.p124-137] 
[43] 
Figueiredo, J.; Serrano, J.L.; Cavalheiro, E.; Keurulainen, L.; Yli-Kauhaluoma, J.; Moreira, V.M.; Ferreira, S.; Domingues, F.C.; Silvestre, S.; Almeida, P. Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents. Eur. J. Med. Chem.,  2018, 143, 829-842.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.070] [PMID:  29223098] 
[44] 
Green, G.R.; Evans, J.M.; Vong, A.K.; Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V. Pyrans and their benzo derivatives synthesis. In: Comprehensive Heterocyclic Chemistry II; Pergamon Press: Oxford, UK, 1995; Vol. 5, p. 469.
[45] 
Abdelrazek, F.M.; Metz, P.; Kataeva, O.; Jäger, A.; El-Mahrouky, S.F. Synthesis and molluscicidal activity of new chromene and pyrano[2,3-c]pyrazole derivatives. Arch. Pharm. (Weinheim),  2007, 340(10), 543-548.
[http://dx.doi.org/10.1002/ardp.200700157] [PMID:  17912679] 
[46] 
Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Synthesis and pharmacological activity of 2-oxo-(2H) 1-benzopyran3-carboxamide derivatives. Eur. J. Med. Chem.,  1993, 28(6), 517-520.
[http://dx.doi.org/10.1016/0223-5234(93)90020-F] 
[47] 
Lei, M.; Ma, L.; Hu, L. A green, efficient, and rapid procedure for the synthesis of 2-amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-one derivatives catalyzed by ammonium acetate. Tetrahedron Lett.,  2011, 52(20), 2597-2600.
[http://dx.doi.org/10.1016/j.tetlet.2011.03.061] 
[48] 
Thetford, D.; Chorlton, A.P.; Hardman, J. Synthesis and properties of some polycyclic barbiturate pigments. Dyes Pigments,  2003, 59(2), 185-191.
[http://dx.doi.org/10.1016/S0143-7208(03)00104-9] 
[49] 
Harriman, G.C.; Brewer, M.; Bennett, R.; Kuhn, C.; Bazin, M.; Larosa, G.; Skerker, P.; Cochran, N.; Gallant, D.; Baxter, D.; Picarella, D.; Jaffee, B.; Luly, J.R.; Briskin, n M.J. Selective cell adhesion inhibitors: Barbituric acid based α4β7--MAdCAM inhibitors. Bioorg. Med. Chem. Lett.,  2008, 18, 2509.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.068] 
[50] 
Daneshvar, N.; Shirini, F.; Langarudi, M.S.N.; Karimi-Chayjani, R. Taurine as a green bio-organic catalyst for the preparation of bio-active barbituric and thiobarbituric acid derivatives in water media. Bioorg. Chem.,  2018, 77, 68-73.
[http://dx.doi.org/10.1016/j.bioorg.2017.12.021] [PMID:  29334621] 
[51] 
Rauf, A.; Shahzad, S.; Bajda, M.; Yar, M.; Ahmed, F.; Hussain, N.; Akhtar, M.N.; Khan, A.; Jończyk, J. Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies. Bioorg. Med. Chem.,  2015, 23(17), 6049-6058.
[http://dx.doi.org/10.1016/j.bmc.2015.05.038] [PMID:  26081763] 
[52] 
Dixit, V.A.; Rathi, P.C.; Bhagat, S.; Gohlke, H.; Petersen, R.K.; Kristiansen, K.; Chakraborti, A.K.; Bharatam, P.V. Design and synthesis of novel Y-shaped barbituric acid derivatives as PPARγ activators. Eur. J. Med. Chem.,  2016, 108, 423-435.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.030] [PMID:  26708109] 
[53] 
Dighore, N.; Anandgaonker, P.; Gaikwad, S.; Rajbhoj, A. Solvent free green synthesis of 5-arylidine barbituric acid derivatives catalyzed by copper oxide nanoparticles. Res. J. Chem. Sci.,  2014, 4(7), 93-98.
[54] 
Rajput, J.K.; Kaur, G. CoFe2O4 nanoparticles: an efficient heterogeneous magnetically separable catalyst for “Click” synthesis of arylidene barbituric acid derivatives at room temperature. Chin. J. Catal.,  2013, 34(9), 1697-1704.
[http://dx.doi.org/10.1016/S1872-2067(12)60646-9] 
[55] 
Shahzad, S.; Shahzadi, L.; Mahmood, N.; Siddiqi, S.A.; Rauf, A.; Manzoor, F.; Chaudhry, A.A. ur Rehman, I.; Yar, M. A new synthetic methodology for the preparation of biocompatible and organo-soluble barbituric-and thiobarbituric acid based chitosan derivatives for biomedical applications. Mater. Sci. Eng. C,  2016, 66, 156-163.
[http://dx.doi.org/10.1016/j.msec.2016.04.056] [PMID:  27207049] 
[56] 
Dhorajiya, B.D.; Dholakiya, B.Z.; Mohareb, R.M. Hybrid probes of aromatic amine and barbituric acid: highly promising leads for anti-bacterial, anti-fungal and anti-cancer activities. Med. Chem. Res.,  2014, 23(9), 3941-3952.
[http://dx.doi.org/10.1007/s00044-014-0973-5] 
[57] 
Darvishzad, S.; Daneshvar, N.; Shirini, F.; Tajik, H. Introduction of piperazine-1, 4-diium dihydrogen phosphate as a new and highly efficient dicationic brönsted acidic ionic salt for the synthesis of (thio) barbituric acid derivatives in water. J. Mol. Struct.,  2019, 1178, 420-427.
[http://dx.doi.org/10.1016/j.molstruc.2018.10.053] 
[58] 
Pourghasemi-Lati, M.; Shirini, F.; Alinia-Asli, M.; Rezvani, M. Butane-1-sulfonic acid immobilized on magnetic Fe3O4@SiO2 nanoparticles: A novel and heterogeneous catalyst for the one-pot synthesis of barbituric acid and pyrano [2, 3-d] pyrimidine derivatives in aqueous media. Appl. Organomet. Chem.,  2018, 32(10) e4455
[http://dx.doi.org/10.1002/aoc.4455] 
[59] 
Ghandi, L.; Miraki, M.K.; Radfar, I.; Yazdani, E.; Heydari, A. Formamidinesulfinic acid‐functionalized Fe3O4@SiO2 as a green and magnetic recyclable catalyst for synthesis of pyrano [2, 3-d] pyrimidinone derivatives. ChemistrySelect,  2018, 3(6), 1787-1792.
[http://dx.doi.org/10.1002/slct.201702887] 
[60] 
Daneshvar, N.; Nasiri, M.; Shirzad, M.; Langarudi, M.S.N.; Shirini, F.; Tajik, H. The introduction of two new imidazole-based bis-dicationic Brönsted acidic ionic liquids and comparison of their catalytic activity in the synthesis of barbituric acid derivatives. New J. Chem.,  2018, 42(12), 9744-9756.
[http://dx.doi.org/10.1039/C8NJ01179F] 
[61] 
Mashhadinezhad, M.; Shirini, F.; Mamaghani, M. Nanoporous Na+-montmorillonite perchloric acid as an efficient heterogeneous catalyst for synthesis of merocyanine dyes based on isoxazolone and barbituric acid. Microporous Mesoporous Mater.,  2018, 262, 269-282.
[http://dx.doi.org/10.1016/j.micromeso.2017.11.031] 
[62] 
Ramisetti, S.R.; Pandey, M.K.; Lee, S.Y.; Karelia, D.; Narayan, S.; Amin, S.; Sharma, A.K. Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells. Eur. J. Med. Chem.,  2018, 143, 1919-1930.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.006] [PMID:  29133035] 
[63] 
Karami, S.; Momeni, A.R.; Albadi, J. Preparation and application of triphenyl (propyl-3-hydrogen sulfate) phosphonium bromide as new efficient ionic liquid catalyst for synthesis of 5-arylidene barbituric acids and pyrano [2, 3-d] pyrimidine derivatives. Res. Chem. Intermed.,  2019, 45(6), 3395-3408.
[http://dx.doi.org/10.1007/s11164-019-03798-0] 
[64] 
Yahyazadehfar, M.; Sheikhhosseini, E.; Ahmadi, S.A.; Ghazanfari, D. Microwave‐associate synthesis of Co3O4 nanoparticles as an effcient nanocatalyst for the synthesis of arylidene barbituric and Meldrum’s acid derivatives in green media. Appl. Organomet. Chem.,  2019, 33(9) e5100
[65] 
Pakravan, N.; Shayani-Jam, H.; Beiginejad, H.; Tavafi, H.; Paziresh, S. A green method for the synthesis of novel spiro compounds: enhancement of antibacterial properties of caffeic acid through electrooxidation in the presence of barbituric acid derivatives. J. Electroanal. Chem.,  2019, 848 113286
[http://dx.doi.org/10.1016/j.jelechem.2019.113286] 
[66] 
Zhang, H-J.; Tian, Y.; Tao, F.R.; Yu, W.; You, K-Y.; Zhou, L-R.; Su, X.; Li, T.D.; Cui, Y-Z. Detection of nitroaromatics based on aggregation induced emission of barbituric acid derivatives. Spectrochim. Acta A Mol. Biomol. Spectrosc.,  2019, 222 117168
[http://dx.doi.org/10.1016/j.saa.2019.117168] [PMID:  31226612] 
[67] 
Alizadeh-Bami, F.; Mehrabi, H.; Ranjbar-Karimi, R. One-pot three-component reaction of arylglyoxals with acetylthiourea and Meldrum’s acid or barbituric acid for synthesis of new 2-acetamido-4-arylthiazol-5-yl derivatives. J. Sulfur Chem.,  2019, 40(5), 1-10.
[http://dx.doi.org/10.1080/17415993.2019.1602127] 
[68] 
Uphade, B.; Gadhave, A. Eggshell waste: an efficient solid catalyst for the synthesisof 5-arylidene barbituric acids under solvent-free condition. IJRST,  2019, 5(4), 1-4.
[69] 
Barakat, A.; Ali, M.; Soliman, S.M.; Abu-Elfotoh, A-M.; Al-Majid, A.M.; Ghabbour, H.A. New hybrid of the barbituric acid motif: synthesis, X-ray single crystal, DFT, and Hirshfeld surface analyses. Res. Chem. Intermed.,  2018, 44(7), 4213-4225.
[http://dx.doi.org/10.1007/s11164-018-3364-6] 
[70] 
Karmakar, A.; Rúbio, G.M.D.M.; Paul, A.; Guedes da Silva, M.F.C.; Mahmudov, K.T.; Guseinov, F.I.; Carabineiro, S.A.C.; Pombeiro, A.J.L. Lanthanide metal organic frameworks based on dicarboxyl-functionalized arylhydrazone of barbituric acid: syntheses, structures, luminescence and catalytic cyanosilylation of aldehydes. Dalton Trans.,  2017, 46(26), 8649-8657.
[http://dx.doi.org/10.1039/C7DT01056G] [PMID:  28650028] 
[71] 
Barakat, A.; Islam, M.S.; Al-Majid, A.M.; Soliman, S.M.; Mabkhot, Y.N.; Al-Othman, Z.A.; Ghabbour, H.A.; Fun, H-K. Synthesis of novel 5-monoalkylbarbiturate derivatives: new access to 1, 2-oxazepines. Tetrahedron Lett.,  2015, 56(50), 6984-6987.
[http://dx.doi.org/10.1016/j.tetlet.2015.10.108] 
[72] 
Uttam, B. A solvent free green protocol for synthesis of 5-arylidine barbituric acid derivatives. Org. Chem. Indian J.,  2016, 12(3), 1-6.
[73] 
Faryabi, M.; Sheikhhosseini, E. Efficient synthesis of novel benzylidene barbituric and thiobarbituric acid derivatives containing ethyleneglycol spacers. J. Indian Chem. Soc.,  2015, 12(3), 427-432.
[http://dx.doi.org/10.1007/s13738-014-0499-2] 
[74] 
Barakat, A.; Al-Majid, A.M.; Al-Ghamdi, A.M.; Mabkhot, Y.N.; Siddiqui, M.R.H.; Ghabbour, H.A.; Fun, H-K. Tandem Aldol-Michael reactions in aqueous diethylamine medium: a greener and efficient approach to dimedone-barbituric acid derivatives. Chem. Cent. J.,  2014, 8(1), 9.
[http://dx.doi.org/10.1186/1752-153X-8-9] [PMID:  24485059] 
[75] 
Szostak, M.; Sautier, B.; Spain, M.; Behlendorf, M.; Procter, D.J. Selective reduction of barbituric acids using SmI2/H2O: synthesis, reactivity, and structural analysis of tetrahedral adducts. Angew. Chem. Int. Ed. Engl.,  2013, 52(48), 12559-12563.
[http://dx.doi.org/10.1002/anie.201306484] [PMID:  24123558] 
[76] 
Rombola, M.; Sumaria, C.S.; Montgomery, T.D.; Rawal, V.H. Development of chiral, bifunctional thiosquaramides: enantioselective Michael additions of barbituric acids to nitroalkenes. J. Am. Chem. Soc.,  2017, 139(15), 5297-5300.
[http://dx.doi.org/10.1021/jacs.7b01115] [PMID:  28375610] 
[77] 
Khazaei, A.; Nik, H.A.A.; Moosavi-Zare, A.R. Water mediated Domino Knoevenagel-Michael-cyclocondensation reaction of malononitrile, various aldehydes and barbituric acid derivatives using boric acid aqueous solution system compared with nano-titania sulfuric acid. J. Chin. Chem. Soc. (Taipei),  2015, 62(8), 675-679.
[http://dx.doi.org/10.1002/jccs.201500115] 
[78] 
Al-Najjar, H.J.; Barakat, A.; Al-Majid, A.M.; Mabkhot, Y.N.; Weber, M.; Ghabbour, H.A.; Fun, H-K. A greener, efficient approach to Michael addition of barbituric acid to nitroalkene in aqueous diethylamine medium. Molecules,  2014, 19(1), 1150-1162.
[http://dx.doi.org/10.3390/molecules19011150] [PMID:  24445342] 
[79] 
Kania, E.; Lubczak, J. New method of synthesis of oligoetherols with pyrimidine ring from barbituric acid and glycidol (Rapid Communication). Polimery,  2014, 59(11-12), 851-854.
[http://dx.doi.org/10.14314/polimery.2014.851] 
[80] 
Kalita, S.J.; Mecadon, H.; Deka, D.C. Reaction of 6-aminouracils with aldehydes in water as both solvent and reactant under FeCl3·6H2O catalysis: towards 5-alkyl/arylidenebarbituric acids. RSC Advances,  2014, 4(61), 32207-32213.
[http://dx.doi.org/10.1039/C4RA03413A] 
[81] 
Mungi, C.V.; Singh, S.K.; Chugh, J.; Rajamani, S. Synthesis of barbituric acid containing nucleotides and their implications for the origin of primitive informational polymers. Phys. Chem. Chem. Phys.,  2016, 18(30), 20144-20152.
[http://dx.doi.org/10.1039/C6CP00686H] [PMID:  27153469] 
[82] 
Terent’ev, A.O.; Vil’, V.A.; Gorlov, E.S.; Rusina, O.N.; Korlyukov, A.A.; Nikishin, G.I.; Adam, W. Selective Oxidative Coupling of 3H‐Pyrazol‐3‐ones, Isoxazol5 (2H)-ones, Pyrazolidine‐3, 5‐diones, and barbituric acids with malonyl peroxides: an effective C-O functionalization. ChemistrySelect,  2017, 2(11), 3334-3341.
[http://dx.doi.org/10.1002/slct.201700720] 
[83] 
Türkel, N.; Aksoy, M.S. Complex formation of Nickel (II) and Copper (II)
with barbituric acid. ISRN Analytical Chemistry,  2014, Article ID 243175
[84] 
Jeong, Y-C.; Anwar, M.; Moloney, M.G.; Bikadi, Z.; Hazai, E. Synthesis, antibiotic activity and structure-activity relationship study of some 3-enaminetetramic acids. Bioorg. Med. Chem. Lett.,  2014, 24(8), 1901-1906.
[http://dx.doi.org/10.1016/j.bmcl.2014.03.013] [PMID:  24679702] 
[85] 
Jeong, Y-C.; Bikadi, Z.; Hazai, E.; Moloney, M.G. A detailed study of antibacterial 3-acyltetramic acids and 3-acylpiperidine-2,4-diones. ChemMed- Chem,  2014, 9(8), 1826-1837.
[http://dx.doi.org/10.1002/cmdc.201402093] [PMID:  24838989] 
[86] 
Shaker, R.M.; Ishak, E.A. Barbituric acid utility in multi-component reactions. Z. Naturforsch,  2011, 66b, 1189-1201.
[http://dx.doi.org/10.1515/znb-2011-1201] 
[87] 
Longo, L.P.; Johnson, B. Treatment of insomnia in substance abusing patients. Psychiatr. Ann.,  1998, 28(3), 154-159.
[http://dx.doi.org/10.3928/0048-5713-19980301-11] 
[88] 
Anderson, J.A.; Dalton, E.R.; Basker, M.A. Insomnia and hypnotherapy. J. R. Soc. Med.,  1979, 72(10), 734-739.
[http://dx.doi.org/10.1177/014107687907201007] [PMID:  399619] 
[89] 
Wikler, A. Diagnosis and treatment of drug dependence of the barbiturate type. Am. J. Psychiatry,  1968, 125(6), 758-765.
[http://dx.doi.org/10.1176/ajp.125.6.758] [PMID:  5698445] 
[90] 
Oshtory, M.A.; Vijayan, N. Clonazepam treatment of insomnia due to sleep myoclonus. Arch. Neurol.,  1980, 37(2), 119-120.
[http://dx.doi.org/10.1001/archneur.1980.00500510077019] [PMID:  7356405] 
[91] 
Krintel, J.J.; Wegmann, F. Aminophylline reduces the depth and duration of sedation with barbiturates. Acta Anaesthesiol. Scand.,  1987, 31(4), 352-354.
[http://dx.doi.org/10.1111/j.1399-6576.1987.tb02582.x] [PMID:  3296607] 
[92] 
Dripps, R.D. Selective utilization of barbiturates as illustrated by a study of butabarbital sodium (NNR). J. Am. Med. Assoc.,  1949, 139(3), 148-150.
[http://dx.doi.org/10.1001/jama.1949.02900200018006] 
[93] 
Hodge, J.; Haskell, B.F.; Rovner, H. Clinical observations with a new non-barbiturate-hypnotic agent (glutethimide) in preoperative sedation and in certain selected patients. Am. J. Surg.,  1957, 94(1), 108-110.
[http://dx.doi.org/10.1016/0002-9610(57)90627-X] [PMID:  13424880] 
[94] 
Lowenstein, D.H.; Aminoff, M.J.; Simon, R.P. Barbiturate anesthesia in the treatment of status epilepticus: clinical experience with 14 patients. Neurology,  1988, 38(3), 395-400.
[http://dx.doi.org/10.1212/WNL.38.3.395] [PMID:  3279338] 
[95] 
Stecker, M.M.; Kramer, T.H.; Raps, E.C.; O’Meeghan, R.; Dulaney, E.; Skaar, D.J. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia,  1998, 39(1), 18-26.
[http://dx.doi.org/10.1111/j.1528-1157.1998.tb01269.x] [PMID:  9578008] 
[96] 
Vining, E.P. Use of barbiturates and benzodiazepines in treatment of epilepsy. Neurol. Clin.,  1986, 4(3), 617-632.
[http://dx.doi.org/10.1016/S0733-8619(18)30966-6] [PMID:  3528811] 
[97] 
Rathee, P.; Tonk, R.; Dalal, A.; Ruhil, M.; Kumar, A. Synthesis and application of thiobarbituric acid derivatives as antifungal agents. Cell. Mol. Biol.,  2016, 62, 3.
[http://dx.doi.org/10.4172/1165-158X.1000141] 
[98] 
Siddiqui, Z.N.; Farooq, F.; Musthafa, T.M.; Ahmad, A.; Khan, A.U. Synthesis, characterization and antimicrobial evaluation of novel halopyrazole derivatives. J. Saudi Chem. Soc.,  2013, 17(2), 237-243.
[http://dx.doi.org/10.1016/j.jscs.2011.03.016] 
[99] 
Sokmen, B.B.; Ugras, S.; Sarikaya, H.Y.; Ugras, H.I.; Yanardag, R. Antibacterial, antiurease, and antioxidant activities of some arylidene barbiturates. Appl. Biochem. Biotechnol.,  2013, 171(8), 2030-2039.
[http://dx.doi.org/10.1007/s12010-013-0486-6] [PMID:  24018846] 
[100] 
Soayed, A.A.; Refaat, H.M.; Sinha, L. Syntheses, structural elucidation, thermal properties, theoretical quantum chemical studies (DFT) and biological studies of barbituric–hydrazone complexes. J. Saudi Chem. Soc.,  2015, 19(2), 217-226.
[http://dx.doi.org/10.1016/j.jscs.2014.05.003] 
[101] 
Elshaier, Y.A.; Barakat, A.; Al-Qahtany, B.M.; Al-Majid, A.M.; Al-Agamy, M.H. Synthesis of pyrazole-thiobarbituric acid derivatives: antimicrobial activity and docking studies. Molecules,  2016, 21(10), 1337.
[http://dx.doi.org/10.3390/molecules21101337] [PMID:  27735850] 
[102] 
Ziarani, G.M.; Faramarzi, S.; Asadi, S.; Badiei, A.; Bazl, R.; Amanlou, M. Three-component synthesis of pyrano[2,3-d]-pyrimidine dione derivatives facilitated by sulfonic acid nanoporous silica (SBA-Pr-SO3H) and their docking and urease inhibitory activity. Daru,  2013, 21(1), 3.
[http://dx.doi.org/10.1186/2008-2231-21-3] [PMID:  23351402] 
[103] 
Paliwal, P.K.; Jetti, S.R.; Jain, S. Green approach towards the facile synthesis of dihydropyrano (c) chromene and pyrano [2, 3-d] pyrimidine derivatives and their biological evaluation. Med. Chem. Res.,  2013, 22(6), 2984-2990.
[http://dx.doi.org/10.1007/s00044-012-0288-3] 
[104] 
Kenchappa, R.; Bodke, Y.D.; Asha, B.; Telkar, S.; Sindhe, M.A. Synthesis, antimicrobial, and antioxidant activity of benzofuran barbitone and benzofuran thiobarbitone derivatives. Med. Chem. Res.,  2014, 23(6), 3065-3081.
[http://dx.doi.org/10.1007/s00044-013-0892-x] 
[105] 
Vosooghi, M.; Farzipour, S.; Saeedi, M.; Shareh, N.B.; Mahdavi, M.; Mahernia, S.; Foroumadi, A.; Amanlou, M.; Shafiee, A. Synthesis of novel 5-arylidene (thio) barbituric acid and evaluation of their urease inhibitory activity. J. Indian Chem. Soc.,  2015, 12(8), 1487-1491.
[http://dx.doi.org/10.1007/s13738-015-0617-9] 
[106] 
El-Zahabi, H.S.A.; Khalifa, M.M.A.; Gado, Y.M.H.; Farrag, A.M.; Elaasser, M.M.; Safwat, N.A.; AbdelRaouf, R.R.; Arafa, R.K. New thiobarbituric acid scaffold-based small molecules: Synthesis, cytotoxicity, 2D-QSAR, pharmacophore modelling and in-silico ADME screening. Eur. J. Pharm. Sci.,  2019, 130, 124-136.
[http://dx.doi.org/10.1016/j.ejps.2019.01.023] [PMID:  30684659] 
[107] 
Fahad, M.M.; Zimam, E.H.; Mohamad, M.J. A series of barbituric acid derivatives from Sulfa drug: synthesis and antimicrobial activity. Nano Biomed. Eng.,  2019, 11(1), 67-83.
[http://dx.doi.org/10.5101/nbe.v11i1.p67-83] 
[108] 
Zhou, K.; Fu, H.; Feng, L.; Cui, M.; Dai, J.; Liu, B. The synthesis and evaluation of near-infrared probes with barbituric acid acceptors for in vivo detection of amyloid plaques. Chem. Commun. (Camb.),  2015, 51(58), 11665-11668.
[http://dx.doi.org/10.1039/C5CC03662C] [PMID:  26103205] 
[109] 
Sattar, M.; Khatun, M. K.; Islam, R.; Sohrab, M. H.; Al-Reza, S. M. Synthesis of barbituric acid derivatives using microwave irradiation method and in vitro evaluation of antimicrobial and cytotoxic activity. J. App. Pharma. Sci.,  2015, 5(11), 038-042.
[http://dx.doi.org/10.7324/JAPS.2015.501106] 
[110] 
Laxmi, S.V.; Rajitha, G.; Rajitha, B.; Rao, A.J. Photochemical synthesis and anticancer activity of barbituric acid, thiobarbituric acid, thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives. J. Chem. Biol.,  2015, 9(2), 57-63.
[http://dx.doi.org/10.1007/s12154-015-0148-y] [PMID:  27118996] 
[111] 
Bhaskarachar, R.K.; Revanasiddappa, V.G.; Hegde, S.; Balakrishna, J.P.; Reddy, S.Y. Design, synthesis and anticancer activity of functionalized spiro-quinolines with barbituric and thiobarbituric acids. Med. Chem. Res.,  2015, 24(9), 3516-3528.
[http://dx.doi.org/10.1007/s00044-015-1408-7] 
[112] 
Bakhotmah, D.A. Synthesis of barbituric and thiobarbituric acids bearing 5, 6-diphenyl-1, 2, 4-triazin-3-yl moiety as CDK2 inhibitors of tumor cells. Amer. J. Heter. Chem.,  2019, 5(4), 76-80.
[113] 
Altowyan, M.S.; Barakat, A.; Soliman, S.M.; Al-Majid, A.M.; Ali, M.; Elshaier, Y.A.; Ghabbour, H.A. A new barbituric acid derivatives as reactive oxygen scavenger: Experimental and theoretical investigations. J. Mol. Struct.,  2019, 1175, 524-535.
[http://dx.doi.org/10.1016/j.molstruc.2018.07.105] 
[114] 
Seyyedi, N.; Shirini, F.; Langarudi, M.S.N. DABCO-based ionic liquids: green and recyclable catalysts for the synthesis of barbituric and thiobarbituric acid derivatives in aqueous media. RSC Advances,  2016, 6(50), 44630-44640.
[http://dx.doi.org/10.1039/C6RA05878G] 
[115] 
Jin, T.S.; Liu, L.B.; Zhao, Y.; Li, T.S. Clean, one pot synthesis of 4H-pyran derivatives catalyzed by hexadecyltrimethyl ammonium bromide in aqueous media. Synth. Commun.,  2005, 35(14), 1859-1863.
[http://dx.doi.org/10.1081/SCC-200064898] 
[116] 
Montazeri, N. Nano Al2O3: an efficient catalyst for the multi-component synthesis of Pyrano [2, 3-d] Pyrimidinone derivatives. Int. J. Nanodimens.,  2015, 6(3), 283-287.
[117] 
Goli-Jolodar, O.; Shirini, F.; Seddighi, M. Succinimidinium hydrogensulfate ([H-Suc] HSO4) as an efficient ionic liquid catalyst for the synthesis of 5-arylidenepyrimidine-2, 4, 6 (1H, 3H, 5H)-trione and pyrano-pyrimidinones derivatives. J. Indian Chem. Soc.,  2016, 12(3), 457-463.
[118] 
Kefayati, H.; Valizadeh, M.; Islamnezhad, A. Green electrosynthesis of pyrano [2, 3-d] pyrimidinones at room temperature. Anal. Bioanal. Electrochem,  2014, 6(1), 80-90.
[119] 
Albadi, J.; Mansournezhad, A.; Sadeghi, T. Eco-friendly synthesis of pyrano [2, 3-d] pyrimidinone derivatives catalyzed by a novel nanocatalyst of ZnO-supported copper oxide in water. Res. Chem. Intermed.,  2015, 41(11), 8317-8326.
[http://dx.doi.org/10.1007/s11164-014-1894-0] 
[120] 
Sabour, B.; Peyrovi, M.H.; Hajimohammadi, M. Al-HMS-20 catalyzed synthesis of pyrano [2, 3-d] pyrimidines and pyrido [2, 3-d] pyrimidines via three-component reaction. Res. Chem. Intermed.,  2015, 41(3), 1343-1350.
[http://dx.doi.org/10.1007/s11164-013-1277-y] 
[121] 
Bhat, A.R.; Dongre, R.S.; Shalla, A.H.; Naikoo, G.A.; Hassan, I.U. Computational analysis for antimicrobial active pyrano [2, 3-d] pyrimidine derivatives on the basis of theoretical and experimental ground. J. Assoc. Arab Univ. Basic Appl. Sci,  2016, 20(1), 19-25.
[http://dx.doi.org/10.1016/j.jaubas.2015.12.004] 
Cite As
Current Organic Chemistry

A Comprehensive Review: Bio-Potential of Barbituric Acid and its Analogues

Abstract

Graphical Abstract
