Efficient Synthetic Access to Novel Indolo[2,3-b]Quinoxaline-based Heterocycles

Ahmed   Abdou O.   Abeed; Talaat      El-Emary; Sarah      Alharthi

doi:10.2174/1570179418666210809144906

Abstract

Background: This paper showed the synthetic capability of the indolo[2,3-b]quinoxaline nucleus to be provided as an excellent precursor for the synthesis of various heterocyclic compounds. These synthetic routes proceed via the formation of 3-(6H-indolo[2,3-b]quinoxalin-6-yl) propane hydrazide (2). The carbohydrazide 2 and its reactions with different reagents give five and six-membered rings, such as 1,3,4-thiadiazole, 1,3,4- oxadiazole, 1,2,4-triazole, and 1,2,4-triazine.

Methods: All chemicals used in the current study were of analytical grade. Melting points were determined using an APP Digital ST 15 melting point apparatus and were uncorrected. FT-IR spectra were recorded on a Pye- Unicam SP3-100 and Shimadzu-408 spectrophotometers in KBr pellets and given in (cm^-1) KBr. The NMR spectra were detected by a Bruker AV-400 spectrometer (400 MHz for ¹H, 100 MHz for ¹³C and 40.55 MHz for ¹⁵N), Institute of Organic Chemistry, Karlsruhe, Germany. Chemical shifts were expressed as δ (ppm) with TMS as an internal reference. Mass spectrometry was provided on a Varian MAT 312 instrument in EI mode (70 eV).

Results: The target compounds were obtained, and their structures were completely elucidated by various spectral and elemental analyses (Ft-IR, ¹H-NMR, ¹³C-NMR, and mass spectrometry).

Conclusion: The current work showed a view of the reactivity of the carbohydrazide group. The carbohydrazide 2 was obtained from the hydrazinolysis of carboethoxy compound 1 and exploited as a key intermediate to synthesize heterocyclic compounds with different rings.

Keywords: Ethyl 3-chloropropionate, indolo[2, 3-b]quinoxaline, carbohydrazide, pyrazole, 1, 3, 4-thiadiazoles, 4-oxadiazoles, 2, 4- triazole.

« Previous Next »

Graphical Abstract

[1] 
Shibinskaya, M.O.; Kutuzova, N.A.; Mazepa, A.V.; Lyakhov, S.A.; Androntai, S.A.; Zubritsky, M.J.; Galat, V.F.; Lipkowski, J.; Kravtsov, V.C. Synthesis of 6-aminopropyl-6H-indolo[2,3-b]quinoxaline derivatives. J. Heterocycl. Chem.,  2012, 49, 678-682.
[http://dx.doi.org/10.1002/jhet.805] 
[2] 
Zhang, H. A green synthesis of indolo [2, 3-b] quinoxaline derivatives. J. Chem. Res.,  2014, 38, 705-709.
[http://dx.doi.org/10.3184/174751914X14146737095013] 
[3] 
Thomas, K.R.J.; Tyagi, P. Synthesis, spectra, and theoretical investigations of the triarylamines based on 6H-indolo [2, 3-b] quinoxaline. J. Org. Chem.,  2010, 75(23), 8100-8111.
[http://dx.doi.org/10.1021/jo1016663] [PMID:  21053895] 
[4] 
Habashneh, A.Y.; El-Abadelah, M.M.; Abadleh, M.M.; Voelter, W. Heterocycles [c]fused onto indoloquinoxaline. Synthesis of novel pyrano [2′,3′:4,5]indolo[2,3-b]quinoxalin-2-ones. Z. Naturforsch.,  2012, 67b, 725-730.
[http://dx.doi.org/10.5560/znb.2012-0131] 
[5] 
Karki, S.S.; Hazare, R.; Kumar, S.; Bhadauria, S.V. Balzarini, j.; Clercq, E. D. Synthesis, anti-cancer and cytostatic activity of some 6H-indolo[2,3-b]quinoxalines. Acta Pharm.,  2009, 59, 431-440.
[http://dx.doi.org/10.2478/v10007-009-0040-9] [PMID:  19919932] 
[6] 
Driller, K.M.; Libnow, S.; Hein, M.; Harms, M.; Wende, K.; Lalk, M.; Michalik, D.; Reinke, H.; Langer, P. Synthesis of 6H-indolo[2,3-b]quinoxaline-N-glycosides and their cytotoxic activity against human ceratinocytes (HaCaT). Org. Biomol. Chem.,  2008, 6(22), 4218-4223.
[http://dx.doi.org/10.1039/b812308j] [PMID:  18972053] 
[7] 
Shibinskaya, M.O.; Karpenko, A.S.; Lyakhov, S.A.; Andronati, S.A.; Zholobak, N.M.; Spivak, N.Y.; Samochina, N.A.; Shafran, L.M.; Zubritsky, M.J.; Galat, V.F. Synthesis and biological activity of 7H-benzo[4,5]indolo[2,3-b]quinoxaline derivatives. Eur. J. Med. Chem.,  2011, 46(2), 794-798.
[http://dx.doi.org/10.1016/j.ejmech.2010.11.040] [PMID:  21172726] 
[8] 
Moorthy, N.S.H.N.; Manivannan, E.; Karthikeyan, C.; Trivedi, P. 6H-Indolo [2, 3-b] quinoxalines: DNA and proteins interacting scaffold for pharmacological activities. Mini Rev. Med. Chem.,  2013, 13, 1-6.
[http://dx.doi.org/10.2174/13895575113139990005] 
[9] 
Wilhelmsson, L.M.; Kingi, N.; Bergman, J. Interactions of antiviral indolo [2, 3-b] quinoxaline derivatives with DNA. J. Med. Chem.,  2008, 51(24), 7744-7750.
[http://dx.doi.org/10.1021/jm800787b] [PMID:  19053744] 
[10] 
Venkateswararao, A.; Tyagi, P.; Thomas, K.R.J.; Chen, P.W.; Ho, K.C. Organic dyes containing indolo[2,3-b]quinoxaline as a donor: synthesis, optical and photo-voltaic properties. Tetrahedron,  2014, 70, 6318-6327.
[http://dx.doi.org/10.1016/j.tet.2014.04.009] 
[11] 
Aly, A.A.; El-Emary, T.I.; Mourad, A.E.; Alyan, Z.Kh.; Bruse, S.; Nieger, M. 5-Carbohydrazide and 5-carbonylazide of pyrazolo[3,4-b]pyridines as reactive intermediates in the synthesis of various heterocyclic derivatives. J. Chem. Res.,  2019, 43, 1-11.
[http://dx.doi.org/10.1177/1747519819861625] 
[12] 
Avula, S.; Komsani, J.R.; Koppireddi, S.; Yadla, R. Microwave-assisted Synthesis 6-{(5-aryl-1, 3, 4-oxadiazol-2-yl) methyl}-6H- indolo[2,3-b]quinoxalines. J. Heterocycl. Chem.,  2015, 52, 1737-1742.
[http://dx.doi.org/10.1002/jhet.2272] 
[13] 
Balandis, B.; Anusevičius, K.; Šiugždaitė, J.; Kantminienė, K.; Mickevičius, V. Synthesis and antibacterial activity of 3-substituted 1-(2-methyl-5-nitrophenyl)-5-oxopyrrolidine derivatives. Res. Chem. Intermed.,  2019, 45, 5499-5517.
[http://dx.doi.org/10.1007/s11164-019-03916-y] 
[14] 
Bhosale, J.D.; Dabur, R.; Jadhav, G.P.; Bendre, R.S. Facile syntheses and molecular docking of novel substituted 3,4-dimethyl-1H-pyrrole-2-carboxamide/carbohydrazide analogues with antimicrobial and antifungal properties. Res. Chem. Intermed.,  2019, 45, 5499-5517.
[15] 
Al-Wahaibi, L.H.; Alvarez, N.; Blacque, O.; Veiga, N.; Al-Mutairi, A.A.; El-Emam, A.A. Synthesis and structure insights of two novel broad spectrum antibacterial candidates based on (E)-N′-[(heteroaryl) methylene]adamantane-1-carbohydrazides. Molecules,  2020, 25(8), 1934-1950.
[http://dx.doi.org/10.3390/molecules25081934] [PMID:  32331284] 
[16] 
Kamat, V.; Santosh, R.; Poojary, B.; Nayak, S.P.; Kumar, B.K.; Sankaranar-ayanan, M. Faheem; Khanapure, Sh.; Barretto, A. D.; Vootla, Sh. K. Pyridine- and thiazole-based hydrazides with promising anti-inflammatory and antimicrobial activities along with their in silico studies. ACS Omega,  2020, 5, 25228-25239.
[http://dx.doi.org/10.1021/acsomega.0c03386] [PMID:  33043201] 
[17] 
Thore, S.N.; Gupta, S.V.; Baheti, K.G. Synthesis and pharmacological evaluation of 5-methyl-2-phenylthiazole-4-substituted heteroazoles as a potential anti-inflammatory and analgesic agents. J. Saudi Chem. Soc.,  2016, 20, S46-S52.
[http://dx.doi.org/10.1016/j.jscs.2012.09.002] 
[18] 
El-Shamy, I.E.; Abdel-Mohsen, A.M.; Als-heikh, A.A.; Fouda, M.M.G.; Al-Deyab, S.S.; El-Hashash, M.A.; Jancar, J. Synthesis, biological, anti-inflammatory activities and quantum chemical calculation of some [4-(2, 4,6-trimethylphenyl)-1(2H)-oxophthalazin-2-yl]acetic acid hydrazide derivatives. Dyes Pigments,  2015, 113, 357-371.
[http://dx.doi.org/10.1016/j.dyepig.2014.08.026] 
[19] 
El-Feky, S.A.H.; Abd El-Samii, Z.K.; Osman, N.A.; Lashine, J.; Kamel, M.A.; Thabet, H. Kh. Synthesis, molecular docking and anti-inflammatory screening of novel quinoline incorporated pyrazole derivatives using the Pfitzinger reaction II. Bioorg. Chem.,  2015, 58, 104-116.
[http://dx.doi.org/10.1016/j.bioorg.2014.12.003] [PMID:  25590381] 
[20] 
Ulloora, S.; Shabaraya, R.; Adhikari, A.V. New 6-bromoimidazo [1,2-a]pyridine-2-carbohydrazide derivatives: Synthesis and anti-convulsant studies. Med. Chem. Res.,  2013, 23, 3019-3028.
[http://dx.doi.org/10.1007/s00044-013-0887-7] 
[21] 
Nayak, N.; Ramprasad, J.; Dalimba, U.; Yogeeswari, P.; Sriram, D. synthesis and antimycobacterial screening of new N-(4-(5-aryl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)phenyl)-4-amide derivatives. Chin. Chem. Lett.,  2016, 27, 365-369.
[http://dx.doi.org/10.1016/j.cclet.2016.01.015] 
[22] 
Abdel-Aziz, H.A.; Elsaman, T.; Al-Dhfyan, A.; Attia, M.I.; Al-Rashood, K.A.; Al-Obaid, A.R. Synthesis and anticancer potential of certain novel 2-oxo-N'-(2-oxoindolin-3-ylidene)-2H-chromene-3-carbohydrazides. Eur. J. Med. Chem.,  2013, 70, 358-363.
[http://dx.doi.org/10.1016/j.ejmech.2013.09.060] [PMID:  24177362] 
[23] 
Zhang, J.; Liu, T.; Chen, M.; Liu, F.; Liu, X.; Zhang, J.; Lin, J.; Jin, Y. Synthesis and biological evaluation of indole-2-carbohydrazide derivatives as anti-cancer agents with anti-angiogenic and anti-proliferative activities. ChemMedChem,  2018, 13(12), 1181-1192.
[http://dx.doi.org/10.1002/cmdc.201800033] [PMID:  29637713] 
[24] 
Naresh Kumar, R.; Poornachandra, Y.; Nagender, P.; Mallareddy, G.; Ravi Kumar, N.; Ranjithreddy, P.; Ganesh Kumar, C.; Narsaiah, B. Synthesis of novel trifluoromethyl substituted furo[2,3-b]pyridine and pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine derivatives as potential anticancer agents. Eur. J. Med. Chem.,  2016, 108, 68-78.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.007] [PMID:  26629861] 
[25] 
Mohareb, R.M.; Wardakhan, W.W.; Abbas, N.S. Synthesis of tetrahydrobenzo[b] thiophene-3-carbohydrazide derivatives as potential anti-cancer agents and pim-1 kinase inhibitors. Anticancer. Agents Med. Chem.,  2019, 19(14), 1737-1753.
[http://dx.doi.org/10.2174/1871520619666190402153429] [PMID:  30947678] 
[26] 
Eldehna, W.M.; Abo-Ashour, M.F.; Al-Warhi, T.; Al-Rashood, S.T.; Alharbi, A.; Ayyad, R.R.; Al-Khayal, K.; Abdulla, M.; Abdel-Aziz, H.A.; Ahmad, R.; El-Haggar, R. Development of 2-oindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells. J. Enzyme Inhib. Med. Chem.,  2021, 36(1), 319-328.
[http://dx.doi.org/10.1080/14756366.2020.1862100] [PMID:  33345633] 
[27] 
Tok, F.; İlhan, R.; Günal, S. Ballar Kirmizi-bayrak, P.; Koçyiğit-Kaymakçioğlu, B. Design, synthesis and evaluation of the biological activities of some new carbohydrazide and urea derivatives. Turk. J. Pharm. Sci.,  2018, 15, 304-308.
[PMID:  32454674] 
[28] 
Pham, V.H.; Phan, T.P.D.; Phan, D.C.; Vu, B.D. Synthesis and bioactivity of hydrazide hydrazones with the 1-adamantyl-carbonyl moiety. Molecules,  2019, 24(21), 1-11.
[http://dx.doi.org/10.3390/molecules24214000] [PMID:  31694218] 
[29] 
Abbas, S.H.; Abd El-Hafeez, A.A.; Shoman, M.E.; Montano, M.M.; Hassan, H.A. New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity. Bioorg. Chem.,  2019, 82, 360-377.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.064] [PMID:  30428415] 
[30] 
Jesumoroti, O.J. Faridoon; Mnkandhla, D.; Isaacs, M.; Hoppe, H. C.; Klein, R. Evaluation of novel N′-(3-hydroxybenzoyl)-2-oxo-2H-chromene-3-carbohydrazide derivatives as potential HIV-1 integrase inhibitors. MedChemComm,  2019, 10, 80-88.
[http://dx.doi.org/10.1039/C8MD00328A] [PMID:  30774857] 
[31] 
Ebrahimzadeh, E.; Tabatabai, S.A.; Vahabpour, R.; Hajimahdi, Z.; Zarghi, A. Design, synthesis, molecular modeling study and biological evaluation of new N′-arylidene pyrido[2,3-d]pyrimidine-5-carbo-hydrazide derivatives as anti-HIV1 agents. Iran. J. Pharm. Res.,  2019, 18(Suppl. 1), 237-248.
[PMID:  32802103] 
[32] 
Abeed, A.A.O.; Jaleel, G.A.A.; Youssef, M.S.K. Novel heterocyclic hybrids based on 2-pyrazoline: Synthesis and assessment of anti-inflammatory and analgesic activities. Curr. Org. Synth.,  2019, 16(6), 921-930.
[http://dx.doi.org/10.2174/1570179416666190703115133] [PMID:  31984913] 
[33] 
Abeed, A.A.O.; El-Emary, T.I.; Youssef, M.S.K. A facile synthesis and reactions of some novel pyrazole-based heterocycles. Curr. Org. Synth.,  2019, 16(3), 405-412.
[http://dx.doi.org/10.2174/1570179416666181210160908] [PMID:  31984902] 
[34] 
Youssef, M.S.K.; Abeed, A.A.O.; El-Emary, T.I. Synthesis and evaluation of chromene-based compounds containing pyrazole moiety as antimicrobial agents. Heterocycl. Commun.,  2017, 23, 55-64.
[http://dx.doi.org/10.1515/hc-2016-0136] 
[35] 
Bakhite, E.A.; Abeed, A.A.O.; Ahmed, O.E.A. Fused thieno[2,3-b]pyridines: synthesis and characterization of new condensed pyridothienopyrimidines. ARKIVOC,  2017, 4, 121-136.
[http://dx.doi.org/10.24820/ark.5550190.p009.991] 
[36] 
Abeed, A.A.O.; Youssef, M.S.K.; Hegazy, R. Synthesis, anti-diabetic and renoprotective activity of some new benzazole, thiazolidin-4-one and azetidin-2-one derivatives. J. Braz. Chem. Soc.,  2017, 28, 2054-2063.
[37] 
Abeed, A.A.O. 2-Pyrazolin-5-one based heterocycles: synthesis and characterization. J. Heterocycl. Chem.,  2015, 5, 1175-1184.
[http://dx.doi.org/10.1002/jhet.2225] 

Rights & Permissions Print Cite

Article Metrics

18

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1570179418666210809144906	Print ISSN 1570-1794
Publisher Name Bentham Science Publisher	Online ISSN 1875-6271

Current Organic Synthesis

Efficient Synthetic Access to Novel Indolo[2,3-b]Quinoxaline-based Heterocycles

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract