Generic placeholder image

Current Traditional Medicine


ISSN (Print): 2215-0838
ISSN (Online): 2215-0846

Review Article

Naturally Available Nitrogen-Containing Fused Heterocyclics as Prospective Lead Molecules in Medicinal Chemistry

Author(s): Nivedita Bhardwaj, Akashdeep Pathania and Pradeep Kumar*

Volume 7, Issue 1, 2021

Published on: 13 June, 2019

Page: [5 - 27] Pages: 23

DOI: 10.2174/2215083805666190613125700

Price: $65


Heterocyclic compounds constitute one of the largest and most versatile families of organic compounds. There are many heterocyclic compounds that are being isolated from natural sources and day by day the number is increasing rapidly due to their enormous utility. Nitrogen containing heterocyclic compounds have a prominent role in medicinal chemistry, biochemistry and other streams of science. In this review, we have covered most of the biologically active nitrogen containing heterocyclic compounds obtained from the natural sources including indole, carbazole, quinoline, isoquinoline and benzothiazole ring system. These isolated nitrogen containing heterocyclic compounds render wide spectrum of biological activities including antifungal, anti-inflammatory, antibacterial, antioxidants, anticonvulsant, anti-allergic, herbicidal and anticancer activities.

Keywords: Heterocyclic compounds, indole, carbazole, quinoline, isoquinoline, benzothiazole.

Graphical Abstract
Hemmerling F, Hahn F. Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides. Beilstein J Org Chem 2016; 12(1): 1512-50.
[] [PMID: 27559404]
Petkowski JJ, Bains W, Seager S. Natural products containing a nitrogen-sulfur bond. J Nat Prod 2018; 81(2): 423-46.
[ PMID: 29364663]
Pozharskii AF, Soldatenkov AT, Katritzky AR. Heterocycles in life and society: An Introduction to Heterocyclic Chememistry.In: Biochemistry and Applications. John Wiley and Sons 2011.
Dickinson BC, Chang CJ. A targetable fluorescent probe for imaging hydrogen peroxide in the mitochondria of living cells. J Am Chem Soc 2008; 130(30): 9638-9.
[] [PMID: 18605728]
Chadha N, Silakari O. Indoles as therapeutics of interest in medicinal chemistry: Bird’s eye view. Eur J Med Chem 2017; 134: 159-84.
[ PMID: 28412530]
Janosik T, Rannug A, Rannug U, Wahlström N, Slätt J, Bergman J. Chemistry and Properties of Indolocarbazoles. Chem Rev 2018; 118(18): 9058-128.
[ PMID: 30191712]
Mandewale MC, Thorat BR, Shelke D, Patil R, Yamgar R. Synthesis, characterization and fluorescence study of N-(E)-(2-hydroxyquinolin-3-yl) methylidene]-1-benzofuran-2-carbohydrazide and ts metal complexes. Heterocycl Lett 2015; 5(2): 251-9.
Bandini M, Eichholzer A. Catalytic functionalization of indoles in a new dimension. Angew Chem Int Ed Engl 2009; 48(51): 9608-44.
[] [PMID: 19946913]
Jacob J, Varghese N, Rasheed SP, Agnihotri S, Sharma V, Wakode S. Recent advances in the synthesis of isoquinoline and its analogue: A review. World J Pharm Pharm Sci 2016; 5: 1821-37.
Gupta A, Rawat S. Synthesis and cyclization of benzothiazole. J Curr Pharm Res 2010; 3: 13-23.
Sundberg R. The Chemistry of Indoles. In: Elsevier 2012.
Andrea P. Book Review: Indole ring synthesis: From natural products to drug discovery. Curr Org Synth 2018; 15(2): 152-3.
Li JJ. Fischer indole synthesis Name Reactions. In: Springer 2014; pp. 253-4.
Li JJ. Name reactions: a collection of detailed mechanisms and synthetic applications. In: Springer Science & Business Media 2010.
Lehmann F, Holm M, Laufer S. Rapid and easy access to indoles via microwave-assisted Hemetsberger-Knittel synthesis. Tetrahedron Lett 2009; 50(15): 1708-9.
Bertoni G. Indolebutyric acid–derived auxin and plant development. Plant Cell 2011; 23(3): 845.
Zhang M-Z, Chen Q, Yang G-F. A review on recent developments of indole-containing antiviral agents. Eur J Med Chem 2015; 89: 421-41.
[ PMID: 25462257]
Johnston PB, Pinter-Brown LC, Warsi G, White K, Ramchandren R. Phase 2 study of everolimus for relapsed or refractory classical Hodgkin lymphoma. Exp Hematol Oncol 2018; 7(12): 12.
[] [PMID: 29774169]
Cai S, Sun S, Peng J, et al. three new indole diketopiperazine alkaloids from Aspergillus taichungensis ZHN-7-07. Tetrahedron 2015; 71(22): 3715-9.
Raja VJ, Lim K-H, Leong C-O, Kam T-S, Bradshaw TD. Novel antitumour indole alkaloid, Jerantinine A, evokes potent G2/M cell cycle arrest targeting microtubules. Invest New Drugs 2014; 32(5): 838-50.
[] [PMID: 24927857]
Meng L, Guo Q, Liu Y, et al. Indole alkaloid sulfonic acids from an aqueous extract of Isatis indigotica roots and their antiviral activity. Acta Pharm Sin B 2017; 7(3): 334-41.
[] [PMID: 28540170]
Bag P, Ojha D, Mukherjee H, et al. A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events. Antiviral Res 2014; 105: 126-34.
[ PMID: 24576908]
Yu H-F, Qin X-J, Ding C-F, et al. Nepenthe-Like Indole Alkaloids with Antimicrobial Activity from Ervatamia chinensis. Org Lett 2018; 20(13): 4116-20.
[] [PMID: 29927253]
Liu L, Chen Y-Y, Qin X-J, et al. Antibacterial monoterpenoid indole alkaloids from Alstonia scholaris cultivated in temperate zone. Fitoterapia 2015; 105: 160-4.
[]] [PMID: 26136061]
Coatti GC, Marcarini JC, Sartori D, Fidelis QC, Ferreira DT, Mantovani MS. Cytotoxicity, genotoxicity and mechanism of action (via gene expression analysis) of the indole alkaloid aspidospermine (antiparasitic) extracted from Aspidosperma polyneuron in HepG2 cells. Cytotechnology 2016; 68(4): 1161-70.
[] [PMID: 25894792]
Hu J-F, Schetz JA, Kelly M, et al. New antiinfective and human 5-HT2 receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea. J Nat Prod 2002; 65(4): 476-80.
[] [PMID: 11975483]
Kanamaru T, Nakano Y, Toyoda Y. iyagawa K-I, Tada M, Kaisho T. In vitro and In vivo Antibacterial Activities of TAK-083, an Agent for Treatment of Helicobacter pylori. Infection. Antimicrob Agents Chemother 2001; 45(9): 2455-9.
[] [PMID: 11502514]
Hurdle JG, O’Neill AJ, Chopra I. Anti-staphylococcal activity of indolmycin, a potential topical agent for control of staphylococcal infections. J Antimicrob Chemother 2004; 54(2): 549-52.
[] [PMID: 15243028]
Cimanga K, De Bruyne T, Pieters L, Vlietinck AJ, Turger CA. In vitro and in vivo antiplasmodial activity of cryptolepine and related alkaloids from Cryptolepis sanguinolenta. J Nat Prod 1997; 60(7): 688-91.
[]] [PMID: 9249972]
Ashok P, Ganguly S, Murugesan S. Manzamine alkaloids: isolation, cytotoxicity, antimalarial activity and SAR studies. Drug Discov Today 2014; 19(11): 1781-91.
[]] [PMID: 24953707]
Lee C, Sohn JH, Jang J-H, et al. Cycloexpansamines A and B: spiroindolinone alkaloids from a marine isolate of Penicillium sp. (SF-5292). J Antibiot (Tokyo) 2015; 68(11): 715-8.
[] [PMID: 25966848]
Duwiejua M, Woode E, Obiri DD. Pseudo-akuammigine, an alkaloid from Picralima nitida seeds, has anti-inflammatory and analgesic actions in rats. J Ethnopharmacol 2002; 81(1): 73-9.
[] [PMID: 12020930]
Kaushik NK, Kaushik N, Attri P, et al. Biomedical importance of indoles. Molecules 2013; 18(6): 6620-62.
[]] [PMID: 23743888]
Kumar S, Singh A, Kumar B, Singh B, Bahadur L, Lal M. Simultaneous quantitative determination of bioactive terpene indole alkaloids in ethanolic extracts of Catharanthus roseus (L.) G. Don by ultra high performance liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 2018; 151: 32-41.
[]] [PMID: 29304410]
Chen Y, Sun L, Du G-H. Reserpine Natural Small Molecule Drugs from Plants. In: Springer 2018; pp. 133-7.
Zhu K, Yang S-N, Ma F-F, Gu X-F, Zhu Y-C, Zhu Y-Z. The novel analogue of hirsutine as an anti-hypertension and vasodilatary agent both in vitro and in vivo. PLoS One 2015; 10(4)e0119477
[] [PMID: 25909998]
Grazulevicius J, Strohriegl P, Pielichowski J, Pielichowski K. Carbazole-containing polymers: synthesis, properties and applications. Prog Polym Sci 2003; 28(9): 1297-353.
Zhao X, Chaudhry ST, Mei J. Heterocyclic building blocks for organic semiconductors. Adv Heterocycl Chem 2017; 121: 133-71.
Yurovskaya M, Alekseyev R. New perspectives on classical heterocyclic reactions involving pyrrole derivatives. Chem Heterocycl Compd 2014; 49(10): 1400-25.
Li JJ. Bucherer carbazole synthesis Name Reactions. In: Springer 2009; pp. 72-3.
Jordan-Hore JA, Johansson CC, Beck EM, Gaunt MJ, Gaunt MJ. Oxidative Pd(II)-catalyzed C-H bond amination to carbazole at ambient temperature. J Am Chem Soc 2008; 130(48): 16184-6.
[] [PMID: 18998652]
Patel OP, Mishra A, Maurya R, et al. Naturally occurring carbazole alkaloids from Murraya koenigii as potential antidiabetic agents. J Nat Prod 2016; 79(5): 1276-84.
[]] [PMID: 27136692]
Yang S-K, Low L-Y, Yap PS-X, Yusoff K, Mai C-W, Lai K-S. Plant-derived antimicrobials: Insights into mitigation of antimicrobial resistance. Rec Nat Prod 2018; 12(4): 295-316.
Husna F, Suyatna FD, Arozal W, Poerwaningsih EH. Anti-Diabetic potential of Murraya koenigii (L.) and its antioxidant capacity in Nicotinamide-Streptozotocin induced diabetic rats. Drug Res (Stuttg) 2018; 68(11): 631-6.
[] [PMID: 29801176]
Itoh T, Hatae N, Nishiyama T, Choshi T, Hibino S, Yoshimura T. Synthesis and cytotoxicity of pyrido 4, 3-b] carbazole alkaloids against HCT-116 and HL-60 cells. Med Chem Res 2018; 27(2): 412-9.
Ng RC, Kassim NK, Yeap YSY, Ee GCL, Yazan SL, Musa KH. Isolation of carbazole alkaloids and coumarins from Aegle marmelos and Murraya koenigii and their antioxidant properties. Sains Malays 2018; 47(8): 1749-56.
Zhang Y, Tangadanchu VKR, Cheng Y, Yang R-G, Lin J-M, Zhou C-H. Potential antimicrobial isopropanol-conjugated carbazole azoles as dual targeting inhibitors of Enterococcus faecalis. ACS Med Chem Lett 2018; 9(3): 244-9.
[]] [PMID: 29541368]
Sharma L. Hepatoprotective effect of Indian herbs and spices in alcohol-induced liver diseases. Int J Green Pharm 2018; 12(02): S315-21. [IJGP.]
Birari R, Roy SK, Singh A, Bhutani KK. Pancreatic lipase inhibitory alkaloids of Murraya koenigii leaves. Nat Prod Commun 2009; 4(8): 1089-92.
[ ] [PMID: 19768989]
Nagappan T, Ramasamy P, Wahid MEA, Segaran TC, Vairappan CS. Biological activity of carbazole alkaloids and essential oil of Murraya koenigii against antibiotic resistant microbes and cancer cell lines. Molecules 2011; 16(11): 9651-64.
[] [PMID: 22105714]
Itoigawa M, Kashiwada Y, Ito C, et al. Antitumor agents. 203. Carbazole alkaloid murrayaquinone A and related synthetic carbazolequinones as cytotoxic agents. J Nat Prod 2000; 63(7): 893-7.
[] [PMID: 10924160]
Thevissen K, Marchand A, Chaltin P, Meert EM, Cammue BP. Antifungal carbazoles. Curr Med Chem 2009; 16(17): 2205-11.
[] [PMID: 19519387]
Wright CW. Plant derived antimalarial agents: New leads and challenges. Phytochem Rev 2005; 4(1): 55-61.
Lastra-Gonzalez G, Manrique CM, Govindarajan G, Whaley-Connell A, Sowers JR. Insights into the emerging cardiometabolic prevention and management of diabetes mellitus. Expert Opin Pharmacother 2005; 6(13): 2209-21.
[] [PMID: 16218882]
Yan H, Mizutani TC, Nomura N, et al. A novel small molecular weight compound with a carbazole structure that demonstrates potent human immunodeficiency virus type-1 integrase inhibitory activity. Antivir Chem Chemother 2005; 16(6): 363-73.
[ ] [PMID: 16329284]
Meragelman KM, McKee TC, Boyd MR. Siamenol, a new carbazole alkaloid from Murraya siamensis. J Nat Prod 2000; 63(3): 427-8.
[] [PMID: 10757740]
Manske RH, Kulka M. The Skraup Synthesis of Quinolines. Org React 2004; 7: 59-98.
Denmark SE, Venkatraman S. On the mechanism of the Skraup-Doebner-Von Miller quinoline synthesis. J Org Chem 2006; 71(4): 1668-76.
[] [PMID: 16468822]
Brouet J-C, Gu S, Peet NP, Williams JD. A Survey of solvents for the conrad-limpach synthesis of 4-hydroxyquinolones. Synth Commun 2009; 39(9): 5193-6.
[]] [PMID: 20046955]
Aly AH, Debbab A, Kjer J, Proksch P. Fungal endophytes from higher plants: A prolific source of phytochemicals and other bioactive natural products. Fungal Divers 2010; 41(1): 1-16.
Marella A, Tanwar OP, Saha R, et al. Quinoline: A versatile heterocyclic. Saudi Pharm J 2013; 21(1): 1-12.
[]] [PMID: 23960814]
O’Donnell F, Smyth TJ, Ramachandran VN, Smyth WF. A study of the antimicrobial activity of selected synthetic and naturally occurring quinolines. Int J Antimicrob Agents 2010; 35(1): 30-8.
[] [PMID: 19748233]
Saifi MA, Beg T, Harrath AH, Altayalan FSH, Al Quraishy S. Antimalarial drugs: Mode of action and status of resistance. Afr J Pharm Pharmacol 2013; 7(5): 148-56.
Kayser O, Kiderlen AF, Croft SL. Natural products as antiparasitic drugs. Parasitol Res 2003; 90(2)(Suppl. 2): S55-62.
[] [PMID: 12937967]
Jain S, Chandra V, Jain PK, Pathak K, Pathak D, Vaidya A. Comprehensive review on current developments of quinoline-based anticancer agents. Arab J Chem in press
Pawar HA. Natural product as a source of lead to the design of new drugs. Nat Prod Chem Res 2014; 2: 6.
Liao L, Liu J, Dreaden EC, et al. A convergent synthetic platform for single-nanoparticle combination cancer therapy: Ratiometric loading and controlled release of cisplatin, doxorubicin, and camptothecin. J Am Chem Soc 2014; 136(16): 5896-9.
[] [PMID: 24724706]
Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J 2011; 10(1): 144.
[] [PMID: 21609473]
Kumar A, Paliwal D, Saini D, Thakur A, Aggarwal S, Kaushik D. A comprehensive review on synthetic approach for antimalarial agents. Eur J Med Chem 2014; 85: 147-78.
[] [PMID: 25084143]
García A, Bocanegra-García V, Palma-Nicolás JP, Rivera G. Recent advances in antitubercular natural products. Eur J Med Chem 2012; 49: 1-23.
[] [PMID: 22280816]
Bassetti M, Dembry LM, Farrel PA, Callan DA, Andriole VT. Comparative antimicrobial activity of gatifloxacin with ciprofloxacin and beta-lactams against gram-positive bacteria. Diagn Microbiol Infect Dis 2001; 41(3): 143-8.
[] [PMID: 11750168]
Gomez CM, Kouznetsov V. Recent developments on antimicrobial quinoline chemistryMicrob Path Strat Combat: Sci Tech Edu 666-77 2013.
Cantrell CL, Schrader KK, Mamonov LK, et al. Isolation and identification of antifungal and antialgal alkaloids from Haplophyllum sieversii. J Agric Food Chem 2005; 53(20): 7741-8.
[] [PMID: 16190626]
Musiol R, Serda M, Hensel-Bielowka S, Polanski J. Quinoline-based antifungals. Curr Med Chem 2010; 17(18): 1960-73.
[] [PMID: 20377510]
Gensler WJ. The synthesis of isoquinolines by the P omeranz-Fritsch reaction. Org React 2004; 6: 191-206.
Heravi MM, Khaghaninejad S, Nazari N. Bischler–Napieralski reaction in the syntheses of isoquinolines. Adv Heterocycl Chem 2014; 112: 183-234.
Wu M, Wang S. An alternative to pictet-gams reaction triggered by hendrickson reagent: isoquinolines and β-carbolines from amides. Synthesis 2010; 2010(04): 587-92.
Obika S, Yasui Y, Yanada R, Takemoto Y. Concise synthesis of the CDE ring system of tetrahydroisoquinoline alkaloids using carbophilic Lewis acid-catalyzed hydroamidation and oxidative Friedel-Crafts cyclization. J Org Chem 2008; 73(13): 5206-9.
[] [PMID: 18529080]
Bentley KW. β-Phenylethylamines and the isoquinoline alkaloids. Nat Prod Rep 2006; 23(3): 444-63.
[]] [PMID: 16741588]
Küpeli E, Koşar M, Yeşilada E, Hüsnü K, Başer C. A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species. Life Sci 2002; 72(6): 645-57.
[] [PMID: 12467905]
Shabbir A, Shahzad M, Arfat Y, Ali L, Aziz RS, Murtaza G. Berberis lycium Royle: A review of its traditional uses, phytochemistry and pharmacology. Afr J Pharm Pharmacol 2012; 6(31): 2346-53.
Martínez-Vázquez M, Estrada-Reyes R, Araujo Escalona AG, et al. Antidepressant-like effects of an alkaloid extract of the aerial parts of Annona cherimolia in mice. J Ethnopharmacol 2012; 139(1): 164-70.
[] [PMID: 22101086]
Kulkarni SK, Dhir A. On the mechanism of antidepressant-like action of berberine chloride. Eur J Pharmacol 2008; 589(1-3): 163-72.
[] [PMID: 18585703]
Neag MA, Mocan A, Echeverría J, et al. Berberine: Botanical occurrence, traditional uses, extraction methods, and relevance in cardiovascular, metabolic, hepatic, and renal disorders. Front Pharmacol 2018; 9(557): 557.
[] [PMID: 30186157]
Iranshahy M, Quinn R, Iranshahi M. Biologically active isoquinoline alkaloids with drug-like properties from the genus Corydalis. RSC Advances 2014; 4(31): 15900-13.
Qing Z-X, Yang P, Tang Q, Cheng P, Liu X-B, Zheng Y-J. Isoquinoline alkaloids and their antiviral, antibacterial, and antifungal activities and structure-activity relationship. Curr Org Chem 2017; 21(18): 1920-34.
Hu R, Li X, Tong Y, Miao D, Pan Q, Jiang Z. Catalyst-free synthesis of 2-arylbenzothiazoles in an air/DMSO oxidant system. Synlett 2016; 27(09): 1387-90.
Gorepatil PB, Mane YD, Ingle VS. Samarium (III) triflate as an efficient and reusable catalyst for facile synthesis of benzoxazoles and benzothiazoles in aqueous medium. Synlett 2013; 24(17): 2241-4.
Sun Y, Jiang H, Wu W, Zeng W, Wu X. Copper-catalyzed synthesis of substituted benzothiazoles via condensation of 2-aminobenzenethiols with nitriles. Org Lett 2013; 15(7): 1598-601.
[] [PMID: 23496117]
Guntreddi T, Vanjari R, Singh KN. Elemental sulfur mediated decarboxylative redox cyclization reaction of o-chloronitroarenes and arylacetic acids. Org Lett 2015; 17(4): 976-8.
[] [PMID: 25634311]
Le Bozec L, Moody CJ. Naturally occurring nitrogen-sulfur compounds. The benzothiazole alkaloids. Aust J Chem 2009; 62(7): 639-47.
Rouf A, Tanyeli C. Bioactive thiazole and benzothiazole derivatives. Eur J Med Chem 2015; 97: 911-27.
[] [PMID: 25455640]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy