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Design, synthesis and in silico evaluation of benzoxazepino(7,6-b)quinolines as potential antidiabetic agents

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Abstract

The second-generation XPhos palladium preformed catalyst-based C–N cross-coupling through Buchwald–Hartwig amination with primary and secondary amines towards functionalized benzoxazepino(7,6-b)quinolines is accounted for. The microwave irradiation in dioxane provided the desired highly functionalized oxazepino quinolines, 5, in high yield and purity from the corresponding 2-chloro-3-formyl quinolines, 1, via intermediate, 4, in a sequential cyclization/Buchwald amination strategy. Besides, functional group tolerance, low catalyst loading, microwave assistance, and a wide scope of reactions are the advantages. Compounds 5a, 5b, 5c, 5d, 5e, and 6j showed 50% inhibition in antioxidant potency, whereas compounds 5f, 5g, 5m, 6h, 6j, and 6k showed potent activity alongside 70% inhibition of alpha-amylase and 50% inhibition of alpha-glucosidase, respectively. The results were supported by molecular docking studies of the active compounds with acarvostatin as a standard drug for antidiabetic activity.

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References

  • Ai Y, Song F-J, Wang S-T, Sun Q, Sun P-H (2010) Molecular modeling studies on 11h-dibenz [b, e] azepine and dibenz [b, f][1, 4] oxazepine derivatives as potent agonists of the human TRPA1 receptor. Molecules 15(12):9364–9379

    CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson KW, Tundel RE, Ikawa T, Altman RA, Buchwald SL (2006) Monodentate phosphines provide highly active catalysts for Pd‐catalyzed C-N bond‐forming reactions of heteroaromatic halides/amines and (H) N‐heterocycles. Ange Chem Int Ed 45(39):6523–6527

    CAS  Google Scholar 

  • Apostolidis E, Lee C (2010) In vitro potential of ascophyllum nodosum phenolic antioxidant‐mediated α‐glucosidase and α‐amylase inhibition. J Food Sci 75(3):97–102

    Google Scholar 

  • Bajaj K, Kumar A (2004) Synthesis and pharmacological evaluation of newer substituted benzoxazepine derivatives as potent anticonvulsant agents. Eur J Med Chem 39(4):369–376

    CAS  PubMed  Google Scholar 

  • Beletskaya I, Averin A, Bessmertnykh A, Denat F, Guilard R (2010) Palladium-catalyzed amination in the synthesis of polyazamacrocycles. Rus J Org Chem 46(7):947–967

    CAS  Google Scholar 

  • Bernfeld P (1955) Amylases, alpha and beta. In: Colowick SP, Kaplan NO (Eds), Methods in Enzymology, vol. 1. Academic Press, New York, pp. 149–158

  • Campiani G, Nacci V, Fiorini I, De Filippis MP, Garofalo A, Ciani SM, Greco G, Novellino E, Williams DC, Zisterer DM (1996) Synthesis, biological activity, and SARs of pyrrolobenzoxazepine derivatives, a new class of specific “peripheral-type” benzodiazepine receptor ligands. J Med Chem 39(18):3435–3450

    CAS  PubMed  Google Scholar 

  • Chandrasekhar S, Seenaiah M, Kumar A, Reddy CR, Mamidyala SK, Kumar CG, Balasubramanian S (2011) Intramolecular copper (I)-catalyzed 1, 3-dipolar cycloaddition of azido-alkynes: synthesis of triazolo-benzoxazepine derivatives and their biological evaluation. Tetrahedron Lett 52(7):806–808

    CAS  Google Scholar 

  • Choudhary S, Pawar AP, Yadav J, Sharma DK, Kant R, Kumar I (2018) One-pot synthesis of chiral tetracyclic dibenzo [b, f][1, 4] oxazepine-fused 1, 2-dihydropyridines (DHPs) under metal-free conditions. J Org Chem 83(16):9231–9239

    CAS  PubMed  Google Scholar 

  • Conejo-García A, García-Rubiño ME, Marchal JA, Núñez MC, Ramírez A, Cimino S, García MÁ, Aránega A, Gallo MA, Campos JM (2011) Synthesis and anticancer activity of (RS)-9-(2, 3-dihydro-1, 4-benzoxaheteroin-2-ylmethyl)-9H-purines. Eur J Med Chem 46(9):3795–3801

    PubMed  Google Scholar 

  • Cross RM, Manetsch R (2010) Divergent route to access structurally diverse 4-quinolones via mono or sequential cross-couplings. J Org Chem 75(24):8654–8657

    CAS  PubMed  Google Scholar 

  • Dardir AH, Melvin PR, Davis RM, Hazari N, Mohadjer Beromi M (2018) Rapidly activating Pd-precatalyst for suzuki–miyaura and buchwald–hartwig couplings of aryl esters. J Org Chem 83(1):469–477

    CAS  PubMed  Google Scholar 

  • Díaz‐Gavilán M, Conejo‐García A, Cruz‐López O, Nunez MC, Choquesillo‐Lazarte D, González‐Pérez JM, Rodríguez‐Serrano F, Marchal JA, Aranega A, Gallo MA (2008a) Synthesis and anticancer activity of (R, S)‐9‐(2, 3‐dihydro‐1, 4‐benzoxathiin‐3‐ylmethyl)‐9H‐purines. Chem Med Chem 3(1):127–135

    PubMed  Google Scholar 

  • Díaz-Gavilán M, Gómez-Vidal JA, Rodríguez-Serrano F, Marchal JA, Caba O, Aránega A, Gallo MA, Espinosa A, Campos JM (2008b) Anticancer activity of (1, 2, 3, 5-tetrahydro-4, 1-benzoxazepine-3-yl)-pyrimidines and-purines against the MCF-7 cell line: preliminary cDNA microarray studies. Bioorg Med Chem Lett 18(4):1457–1460

    PubMed  Google Scholar 

  • Friis SD, Skrydstrup T, Buchwald SL (2014) Mild Pd-catalyzed aminocarbonylation of (hetero) aryl bromides with a palladacycle precatalyst. Org Lett 16(16):4296–4299

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ghandi M, Zarezadeh N, Abbasi A (2016) One-pot tandem Ugi-Ar approach to highly functionalized quino [2, 3-b][1, 5] benzoxazepines. Mol Diver 20(2):483–495

    CAS  Google Scholar 

  • Gijsen HJ, Berthelot D, Zaja M, Brône B, Geuens I, Mercken M (2010) Analogues of morphanthridine and the tear gas dibenz [b, f][1, 4] oxazepine (CR) as extremely potent activators of the human transient receptor potential ankyrin 1 (TRPA1) channel. J Med Chem 53(19):7011–7020

    CAS  PubMed  Google Scholar 

  • Greene L, Butini S, Campiani G, Williams D, Zisterer D (2016) Pre-clinical evaluation of a novel class of anti-cancer agents, the pyrrolo-1, 5-benzoxazepines. J Cancer 7(15):2367

    CAS  PubMed  PubMed Central  Google Scholar 

  • Greenwood J, Steinman L, Zamvil SS (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6(5):358

    CAS  PubMed  Google Scholar 

  • Guo S, Zhong X, Gong B, Cui H, Xiang J (2016) Synthesis of pyrido [2, 3-b][1, 4] benzoxazepines via a Friedel−Crafts cyclization. Chem Heterocyl Com 52(5):326–330

    CAS  Google Scholar 

  • Henderson JL, McDermott SM, Buchwald SL (2010) Palladium-catalyzed amination of unprotected halo-7-azaindoles. Org Lett 12(20):4438–4441

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hooper MW, Utsunomiya M, Hartwig JF (2003) Scope and mechanism of palladium-catalyzed amination of five-membered heterocyclic halides. J Org Chem 68(7):2861–2873

    CAS  PubMed  Google Scholar 

  • Ikawa T, Barder TE, Biscoe MR, Buchwald SL (2007) Pd-catalyzed amidations of aryl chlorides using monodentate biaryl phosphine ligands: a kinetic, computational, and synthetic investigation. J Am Chem Soc 129(43):13001–13007

    CAS  PubMed  Google Scholar 

  • Kalek M, Ziadi A, Stawinski J (2008) Microwave-assisted palladium-catalyzed cross-coupling of aryl and vinyl halides with H-phosphonate diesters. Org Lett 10(20):4637–4640

    CAS  PubMed  Google Scholar 

  • Kamei K, Maeda N, Nomura K, Shibata M, Katsuragi-Ogino R, Koyama M, Nakajima M, Inoue T, Ohno T, Tatsuoka T (2006) Synthesis, SAR studies, and evaluation of 1, 4-benzoxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: Discovery of Piclozotan. Bio Org Med Chem 14(6):1978–1992

    CAS  Google Scholar 

  • Louie J, Hartwig JF (1995) Palladium-catalyzed synthesis of arylamines from aryl halides. Mechanistic studies lead to coupling in the absence of tin reagents. Tetrahedron Lett 36(21):3609–3612

    CAS  Google Scholar 

  • Mc Gee MM, Hyland E, Campiani G, Ramunno A, Nacci V, Zisterer DM (2002) Caspase‐3 is not essential for DNA fragmentation in MCF‐7 cells during apoptosis induced by the pyrrolo‐1, 5‐benzoxazepine, PBOX‐6. FEBS lett 515(1–3):66–70

    Google Scholar 

  • Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comp Chem 30(16):2785–2791

    CAS  Google Scholar 

  • Nair SS, Kavrekar V, Mishra A (2013) In vitro studies on alpha amylase and alpha glucosidase inhibitory activities of selected plant extracts. Eur J Exp Biol 3(1):128–132

    Google Scholar 

  • Neochoritis CG, Tsoleridis CA, Stephanidou-Stephanatou J, Kontogiorgis CA, Hadjipavlou-Litina DJ (2010) 1, 5-Benzoxazepines vs 1, 5-benzodiazepines. One-pot microwave-assisted synthesis and evaluation for antioxidant activity and lipid peroxidation inhibition. J Med Chem 53(23):8409–8420

    CAS  PubMed  Google Scholar 

  • Nilsson PK, Olofsson K, Larhed M (2006) Microwave-assisted and metal-catalyzed coupling reactions. In Microwave Methods Org Synthesis 103–144. (Springer, Berlin, Heidelberg)

  • Old DW, Harris MC, Buchwald SL (2000) Efficient palladium-catalyzed N-arylation of indoles. Org Lett 2(10):1403–1406

    CAS  PubMed  Google Scholar 

  • Oshimoto K, Zhou B, Tsuji H, Kawatsura M (2020) Synthesis of substituted benzo [b][1, 4] oxazepine derivatives by the reaction of 2-aminophenols with alkynones. Org Biomol Chem 18(3):415–419

    CAS  PubMed  Google Scholar 

  • Prabakaran K, Manivel P, Khan FN (2010) An effective BINAP and microwave accelerated palladium-catalyzed amination of 1-chloroisoquinolines in the synthesis of new 1, 3-disubstituted isoquinolines. Tetrahedron Lett 51(33):4340–4343

    CAS  Google Scholar 

  • Qin X, Ren L, Yang X, Bai F, Wang L, Geng P, Bai G, Shen Y (2011) Structures of human pancreatic α-amylase in complex with acarviostatins: Implications for drug design against type II diabetes. J Struct Biol 174(1):196–202

    CAS  PubMed  Google Scholar 

  • Ramírez A, Conejo-García A, Griñán-Lisón C, López-Cara LC, Jimenez G, Campos JM, Marchal JA, Boulaiz H (2018) Enhancement of tumour cell death by combining gef gene mediated therapy and new 1, 4-benzoxazepin-2, 6-dichloropurine derivatives in breast cancer cells. Front Pharm 9:798

    Google Scholar 

  • Ranasinghen N, Mongeau E, Yuan G, Minden Z, Waldron S, Patrick C, Fouad F, Kappera S, Jones GB (2017) Flow and Microwave Induced Pellizzari Reactions: Synthesis of Heterocyclic Analogues of the Benzoxazepine Antipsychotic Agents Loxapine and JL-13, Article ID 8147421

  • Riedmueller S, Kaufhold O, Spreitzer H, Nachtsheim BJ (2014) Synthesis of sterically congested triarylamines by palladium‐catalyzed amination. Eur J Org Chem 2014(7):1391–1394

    CAS  Google Scholar 

  • Roig-Zamboni V, Cobucci-Ponzano B, Iacono R, Ferrara MC, Germany S, Bourne Y, Parenti G, Moracci M, Sulzenbacher G (2017) Structure of human lysosomal acid α-glucosidase–a guide for the treatment of Pompe disease. Nat Commun 8(1):1111

    PubMed  PubMed Central  Google Scholar 

  • Ruiz-Castillo P, Buchwald SL (2016) Applications of palladium-catalyzed C–N cross-coupling reactions. Chem Rev 116(19):12564–12649

    CAS  PubMed  PubMed Central  Google Scholar 

  • Singh UK, Strieter ER, Blackmond DG, Buchwald SL (2002) Mechanistic insights into the Pd (BINAP)-catalyzed amination of aryl bromides: Kinetic studies under synthetically relevant conditions. J Am Chem Soc 124(47):14104–14114

    CAS  PubMed  Google Scholar 

  • Sivaraj S, Kannayiram G, Dasararaju G (2017) Evaluation of antidiabetic activity of different extracts of Myristica fragrans houtt: In vitro and in silico studies. Asian J Pharm Clin Res 10(4):275–277

    CAS  Google Scholar 

  • Sole D, Mariani F (2013) Synthesis of dibenzo [b, e] azepin-11-ones by intramolecular palladium-catalyzed acylation of aryliodides with aldehydes. J Org Chem 78(16):8136–8142

    CAS  PubMed  Google Scholar 

  • Sonar SS, Sadaphal SA, Pawar SS, Shingate BB, Shingare MS (2009a) Microwave assisted convenient synthesis of quino [2, 3-b][1, 5] benzoxazepines. Chin Chem Lett 20(5):557–561

    CAS  Google Scholar 

  • Sonar SS, Sadaphal SA, Shitole NV, Jogdand NR, Shingate BB, Shingare MS (2009b) Alum Catalyzed Convenient Synthesis of Quino[2,3-b][1,5 benzoxazepine α-Aminophosphonate Derivatives. Bull Kor Chem Soc 30(8):1711–1714

    CAS  Google Scholar 

  • Sonar SS, Sadaphal SA, Labade VB, Shingate BB, Shingare MS (2009c) An efficient synthesis and antibacterial screening of novel oxazepine α-aminophosphonates by ultrasound approach. Phosphorus, Sulfur, Silicon 185(1):65–73

    Google Scholar 

  • Surry DS, Buchwald SL (2011) Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide. Chem Sci 2(1):27–50

    CAS  PubMed  PubMed Central  Google Scholar 

  • Topchiy MA, Asachenko AF, Nechaev MS (2014) Solvent‐free Buchwald–Hartwig reaction of aryl and heteroaryl halides with secondary amines. Eur J Org Chem 2014(16):3319–3322

    CAS  Google Scholar 

  • Tundel RE, Anderson KW, Buchwald SL (2006) Expedited palladium-catalyzed amination of aryl nonaflates through the use of microwave-irradiation and soluble organic amine bases. J Org Chem 71(1):430–433

    CAS  PubMed  Google Scholar 

  • Wan Y, Alterman M, Hallberg A (2002) Palladium-catalyzed amination of aryl bromides using temperature-controlled microwave heating. Synthesis 2002(11):1597–1600

    Google Scholar 

  • Wang Y, Liang H, Chen C, Wang D, Peng J (2015) One-pot synthesis of quinolin-4 (1H)-one derivatives by a sequential michael addition–elimination/palladium-catalyzed Buchwald–Hartwig amination reaction. Synthesis 47(13):1851–1860

    CAS  Google Scholar 

  • Wang T, Magnin DR, Hamann LG (2003) Palladium-catalyzed microwave-assisted amination of 1-bromonaphthalenes and 5-and 8-bromoquinolines. Org Lett 5(6):897–900

    CAS  PubMed  Google Scholar 

  • Youssef K, Said M (1996) Synthesis of some novel derivatives of 1, 4-benzoxazepine-3, 5-diones as anticonvulsant agents. Egypt J Pharm Sci 37(1–6):45–55

    CAS  Google Scholar 

  • Zahratunnisa N, Elya B, Noviani A (2017) Inhibition of Alpha-Glucosidase and Antioxidant Test of Stem Bark Extracts of Garcinia fruticosa Lauterb. Pharmacogn J 9(2):273–275

    CAS  Google Scholar 

  • Zhou T, Li G, Nolan SP, Szostak M (2019) [Pd (NHC)(acac) Cl]: well-defined, air-stable, and readily available precatalysts for Suzuki and Buchwald–Hartwig cross-coupling (TRansamidation) of amides and esters by N–C/O–C activation. Org Lett 21(9):3304–3309

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to express their gratitude to the Vellore Institute of Technology, Vellore for support and SIF-VIT for facilitating analytical support. The authors thank Syngene International Limited, Bengaluru for their extended support.

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Authors and Affiliations

  1. Organic and Medicinal Chemistry Research Laboratory, School of Advanced Sciences, Vellore Institute of Technology, Vellore, 632 014, Tamil Nadu, India

    Pandurangan Thiyagamurthy, Chitrala Teja & Fazlur-Rahman Nawaz Khan

  2. Department of Pharmaceutical Chemistry, G. Pulla Reddy College of Pharmacy, Hyderabad, 500 028, Telangana, India

    Kondapalli Naresh

  3. Dr. MGR Educational Research Institute, Chennai, 600095, Tamil Nadu, India

    K. Gomathi

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  1. Pandurangan Thiyagamurthy
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Thiyagamurthy, P., Teja, C., Naresh, K. et al. Design, synthesis and in silico evaluation of benzoxazepino(7,6-b)quinolines as potential antidiabetic agents. Med Chem Res 29, 1882–1901 (2020). https://doi.org/10.1007/s00044-020-02606-4

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