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Design, synthesis, and pharmacological evaluation of [1, 3] dioxolo-chromeno[2,3-b]pyridines as anti-seizure agents

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Abstract

An efficient one-pot three-component reaction for the synthesis of [1,3]dioxolo[4′,5′:6,7]chromeno[2,3-b]pyridines 4(a–i) has been developed. Synthesis was achieved by reacting sesamol (1), aromatic aldehydes 2(a–i), and 2-aminopropene-1,1,3-tricarbonitrile (3) in the presence of triethylamine at 100 °C under neat reaction condition. Simple operational procedure, broad substrate scope, column chromatography free separations, and high yield of products make it an efficient and largely acceptable synthetic strategy. Synthesized compounds 4(a–i) were further screened for preliminary anticonvulsant activity using MES and scPTZ tests. These analogs were also checked for neurotoxicity and hepatotoxicity. Selected active compounds have been then screened quantitatively to determine ED50 and TD50 values. Analog 4h was found effective in both preclinical seizure models with significant therapeutic/toxicity profile (4h: ED50 = 34.7 mg/kg, MES test; ED50 = 37.9 mg/kg, scPTZ test; TD50 = 308.7 mg/kg). Molecular dynamic simulation for 100 ns of compound 4h-complexed with GABAA receptor revealed good thermodynamic behavior and fairly stable interactions (4h, Docking score =  − 10.94). In conclusion, effective synthetic strategy, significant anticonvulsant activity with good toxicity profile and detailed molecular modeling studies led us to anticipate the emergence of these analogs as valid leads for the development of future effective neurotherapeutic agents.

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References

  1. Raveesha R, Kumar KY, Raghu MS, Prasad SB, Alsalme A, Krishnaiah P, Prashanth MK (2022) Synthesis, in silico ADME, toxicity prediction and molecular docking studies of N-substituted [1,2,4] triazolo [4,3-a] pyrazine derivatives as potential anticonvulsant agents. J Mol Struct 1257:132587

    Google Scholar 

  2. Ugale VG, Bari SB (2014) Quinazolines: new horizons in anticonvulsant therapy. Eur J Med Chem 80:447–501

    Article  CAS  PubMed  Google Scholar 

  3. Pal R, Akhtar MJ, Raj K, Singh S, Sharma P, Kalra S, Chawla PA, Kumar B (2022) Design, synthesis and evaluation of piperazine clubbed 1,2,4-triazine derivatives as potent anticonvulsant agents. J Mol Struct 1257:132587

    Article  CAS  Google Scholar 

  4. Grover G, Nath R, Bhatia R, Akhtar MJ (2020) Synthetic and therapeutic perspectives of nitrogen containing heterocycles as anticonvulsants. Bioorg Med Chem 28:115585

    Article  CAS  PubMed  Google Scholar 

  5. Pal R, Singh K, Khan SA, Chawla P, Kumar B, Akhtar MJ (2021) Reactive metabolites of the anticonvulsant drugs and approaches to minimize the adverse drug reaction. Eur J Med Chem 226:113890

    Article  CAS  PubMed  Google Scholar 

  6. Kennedy GM, Lhatoo SD (2008) CNS adverse events associated with antiepileptic drugs. CNS Drugs 22:739–760

    Article  CAS  PubMed  Google Scholar 

  7. Cramer JA, Mintzer S, Wheless J, Mattson RH (2010) Adverse effects of antiepileptic drugs: a brief overview of important issues. Expert Rev Neurother 10:885–891

    Article  CAS  PubMed  Google Scholar 

  8. Sarco DP, Bourgeois BF (2010) The safety and tolerability of newer antiepileptic drugs in children and adolescents. CNS Drugs 24:399–430

    Article  CAS  PubMed  Google Scholar 

  9. Srivastava SK, Tripathi RP, Ramachandran R (2005) NAD+ dependent DNA ligase (Rv3014c) from Mycobacterium tuberculosis: crystal structure of the adenylation domain and identification of novel inhibitors. J Biol Chem 280:30273–30281

    Article  CAS  PubMed  Google Scholar 

  10. Brotz-Oesterhelt H, Knezevic I, Bartel S, Lampe T, Warnecke-Eberz U, Ziegelbauer K, Habich D, Labischinski H (2003) Specific and potent inhibition of NAD+ dependent DNA ligase by pyridochromanones. J Biol Chem 278:39435–39442

    Article  PubMed  Google Scholar 

  11. Kolokythas G, Pouli N, Marakos P, Pratsinis H, Kletsas D (2006) Design, synthesis and antiproliferative activity of some new azapyranoxanthenone amino derivatives. Eur J Med Chem 41:71–79

    Article  CAS  PubMed  Google Scholar 

  12. Azuine MA, Tokuda H, Takayasu J, Enjyo F, Mukainaka T, Konoshima T, Nishino H, Kapadia GJ (2004) Cancer chemopreventive effect of phenothiazines and related tri-heterocyclic analogues in the 12-O-tetradecanoylphorbol-13-acetate promoted Epstein-Barr virus early antigen activation and the mouse skin two-stage carcinogenesis models. Pharmacol Res 49:161–169

    Article  CAS  PubMed  Google Scholar 

  13. Oset-Gasque MG, Gonzáles MP, Péres-Peña JP, Garcia-Font N, Romero A, del Pino J, Ramos E, Hadjipavlou-Litina D, Soriano E, Chioua M, Samadi A, Raghuvanshi DS, Singh KM, Marco-Contelles J (2014) Toxicological and pharmacological evaluation, antioxidant, ADMET and molecular modeling of selected racemic chromenotacrines 11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ols for the potential prevention and treatment of Alzheimer’s disease. Eur J Med Chem 74:491–501

    Article  CAS  PubMed  Google Scholar 

  14. Ukawa K, Ishiguro T, Kuriki H, Nohara A (1985) Synthesis of the metabolites and degradation products of 2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b] pyridine-3-carboxylic Acid (Amoxanox). Chem Pharm Bull 33:4432–4437

    Article  CAS  Google Scholar 

  15. Makino H, Saijo T, Ashida Y, Kuriki H, Maki Y (1987) Mechanism of action of an antiallergic agent, Amlexanox (AA-673), in inhibiting histamine release from mast cells. Int Arch Allergy Appl Immunol 82:66–71

    Article  CAS  PubMed  Google Scholar 

  16. Maeda A, Tsuruoka S, Kanai Y, Endou H, Saito K, Miyamoto A, Fujimura A (2008) Evaluation of the interaction between nonsteroidal anti-inflammatory drugs and methotrexate using human organic anion transporter 3-transfected cells. Eur J Pharmacol 596:166–172

    Article  CAS  PubMed  Google Scholar 

  17. Anderson DR, Hegde S, Reinhard E, Gomez L, Vernier WF, Sambandam A, Snider PA (2005) Aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem Lett 15:1587–1590

    Article  CAS  PubMed  Google Scholar 

  18. Elinson MN, Vereshchagin AN, Anisina YE, Egorov MP (2020) Efficient multicomponent approach to the medicinally relevant 5-aryl-chromeno[2,3-b]pyridine scaffold. Polycycl Aromat Compd 40:108–115

    Article  CAS  Google Scholar 

  19. Elinson MN, Vereshchagin AN, Anisina YE, Krymov SK, Fakhrutdinov AN, Egorov MP (2019) Selective multicomponent ‘one-pot’ approach to the new 5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)chromeno[2,3-b]pyridine scaffold in pyridine–ethanol catalyst/solvent system. Mon Chem 150:1073–1078

    Article  CAS  Google Scholar 

  20. Elinson M, Vereshchagin A, Anisina Y, Krymov S, Fakhrutdinov A, Egorov M (2019) Potassium fluoride catalysed multicomponent approach to medicinally privileged 5-[3-hydroxy-6-(hydroxymethyl)-4H-pyran-2-yl] substituted chromeno[2,3-b]pyridine scaffold. ARKIVOC II:38–49

    Article  Google Scholar 

  21. Vereshchagin AN, Elinson MN, Anisina YE, Ryzhkov FV, Goloveshkin AS, Novikov RA, Egorov MP (2017) Synthesis, structural, spectroscopic and docking studies of new 5C-substituted 2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitriles. J Mol Struct 1146:766–772

    Article  CAS  Google Scholar 

  22. Elinson MN, Ryzhkov FV, Korolev VA, Egorov MP (2016) Pot, atom and step-economic (PASE) synthesis of medicinally relevant spiro[oxindole-3,4′-pyrano[4,3-b]pyran] scaffold. Heterocycl Commun 22:11–15

    Article  CAS  Google Scholar 

  23. Elinson MN, Nasybullin RF, Ryzhkov FV, Zaimovskaya TA, Nikishin GI (2015) Solvent-free and ‘on-water’ multicomponent assembling of aldehydes, 3-methyl-2-pyrazoline-5-one, and malononitrile: fast and efficient approach to medicinally relevant pyrano[2,3-c]pyrazole scaffold. Mon Chem 146:631–635

    Article  CAS  Google Scholar 

  24. Mishra S, Ghosh R (2012) K2CO3-mediated, one-pot, multicomponent synthesis of medicinally potent pyridine and chromeno[2,3-b]pyridine scaffolds. Synth Commun 42:2229–2244

    Article  CAS  Google Scholar 

  25. Evdokimov NM, Kireev AS, Yakovenko AA, Antipin MY, Magedov IV, Kornienko A (2006) Convenient one-step synthesis of a medicinally relevant benzopyranopyridine system. Tetrahedron Lett 47:9309–9312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bojase G, Wanjala CCW, Majinda RRT (2001) Flavonoids from the stem bark of Bolusanthus speciosus. Phytochemistry 56:837–841

    Article  CAS  PubMed  Google Scholar 

  27. de Rezende LC, Juck DBF, David JM, David JP, Lima MVB, Lima LS, Alves CQ (2015) New flavans isolated from the leaves and stems of Cratylia mollis (Leguminosae). Phytochem Lett 14:165–169

    Article  Google Scholar 

  28. Latif Z, Hartley TG, Rice MJ, Waigh RD, Waterman PG (1998) Novel and insecticidal isobutylamides from Dinosperma erythrococca. J Nat Prod 61:614–619

    Article  CAS  PubMed  Google Scholar 

  29. Awouafack MD, Tchuenguem RT, Ito T, Dzoyem JP, Tane P, Morita H (2016) A new isoflavanol from the fruits of Kotschya strigosa (Fabaceae). Helv Chim Acta 99:321–324

    Article  CAS  Google Scholar 

  30. Huang D, Zhu H, Chen Y, Chen W, Xue D, Sun L (2015) Prenylated phenylpropanoid compounds from the stem bark of Illicium burmanicum. Fitoterapia 107:22–28

    Article  CAS  PubMed  Google Scholar 

  31. Katritzky AR, Kulshyn OV, Stoyanova-Slavova I, Dobchev DA, Kuanar M, Fara DC, Karelson M (2006) Antimalarial activity: a QSAR modeling using CODESSA PRO software. Bioorg Med Chem 14:2333–2357

    Article  CAS  PubMed  Google Scholar 

  32. Ugale VG, Bari SB, Khadse SC, Reddy PN, Bonde CG, Chaudhari PJ (2020) Exploring quinazolinones as anticonvulsants by molecular fragmentation approach: structural optimization, synthesis and pharmacological evaluation studies. ChemistrySelect 5:2902–2912

    Article  CAS  Google Scholar 

  33. Ugale VG, Bari SB (2016) Structural exploration of quinazolin-4(3H)-ones as anticonvulsants: rational design, synthesis, pharmacological evaluation, and molecular docking studies. Arch Pharm Chem Life Sci 349:864–880

    Article  CAS  Google Scholar 

  34. Nikalje AP, Ansari A, Bari SB, Ugale VG (2015) Synthesis, biological activity, and docking study of novel isatin coupled thiazolidin-4-one derivatives as anticonvulsants. Arch Pharm Chem Life Sci 348:433–445

    Article  CAS  Google Scholar 

  35. Ugale VG, Bari SB (2016) Identification of potential Gly/NMDA receptor antagonists by cheminformatics approach: a combination of pharmacophore modeling, virtual screening and molecular docking studies. SAR QSAR Environ Res 27:125–145

    Article  CAS  PubMed  Google Scholar 

  36. Ugale VG, Patel HM, Wadodkar SG, Bari SB, Shirkhedkar AA, Surana SJ (2012) Quinazolino-benzothiazoles: fused pharmacophores as anticonvulsant agents. Eur J Med Chem 53:107–113

    Article  CAS  PubMed  Google Scholar 

  37. Ugale VG, Wani R, Khadse SC, Bari SB (2020) N-methyl-d-aspartate receptor antagonists: emerging drugs to treat neurodegenerative diseases. In: Biochemistry, biophysics and molecular chemistry: applied research interaction. Routledge, London, p 14

  38. Stables JP, Kupferberg HJ (1997) The NIH anticonvulsant drug development (ADD) program: preclinical anticonvulsant screening project. In: Avanzini G, Tanganelli P, Avoli M (eds) Molecular and cellular targets for antiepileptic drugs. John Libbey & Co., Ltd., London, pp 191–198

    Google Scholar 

  39. Yogeeswari P, Sriram D, Thirumurugan R, Raghavendran JV, Sudhan K, Pavana RK, Stables J (2005) Discovery of N-(2,6-dimethylphenyl)-substituted semicarbazones as anticonvulsants: hybrid pharmacophore-based design. J Med Chem 48:6202–6211

    Article  CAS  PubMed  Google Scholar 

  40. Hammer H, Bader BM, Ehnert C, Bundgaard C, Bunch L, Hoestgaard-Jensen K, Schroeder OH, Bastlund JF, Gramowski-Voß A, Jensen AA (2015) A multifaceted GABAA receptor modulator: functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude). Mol Pharmacol 88(2):401–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zayed MF, Ihmaid SK, Ahmed HE, El-Adl K, Asiri AM, Omar AM (2017) Synthesis, modelling, and anticonvulsant studies of new quinazolines showing three highly active compounds with low toxicity and high affinity to the GABA-A receptor. Molecules 22(2):188

    Article  PubMed  PubMed Central  Google Scholar 

  42. Swinyard EA (1989) General Principles: experimental selection, quantification, and evaluation of antiepileptic drugs, 4th edn. Raven Press, New York

    Google Scholar 

  43. White HS, Johnson M, Wolf H, Kupferberg H (1995) The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. Ital J Neurol Sci 16:73–77

    Article  CAS  PubMed  Google Scholar 

  44. White HS, Woodhead JH, Wilcox KS, Stables JP, Kupferberg HJ, Wolf HH (2002) Discovery and preclinical development of antiepileptic drugs, 5th edn. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  45. Firke SD, Cheke RS, Ugale VG, Khadse SC, Gagarani MB, Bari SB, Surana SJ (2021) Rationale design, synthesis, and pharmacological evaluation of isatin analogues as antiseizure agents. Lett Drug Des Discov 18:1146–1164

    Article  CAS  Google Scholar 

  46. Giardina WJ, Gasior M (2009) Acute seizure tests in epilepsy research: electroshock and chemical induced convulsions in the mouse. Curr Protoc Pharmacol S 45:5–22

    Google Scholar 

  47. Schrödinger, LLC (2009) LigPrep, version 2.3. Schrödinger, LLC, New York

  48. Schrödinger, LLC (2009) Glide, version 5.5. Schrödinger, LLC, New York

  49. Masiulis S, Desai R, Uchański T, Serna I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J (2019) GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature 565:454–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dhote AM, Patil VR, Lokwani DK, Amnerkar ND, Ugale VG, Charbe NB, Bhongade BA, Khadse SC (2021) Strategic analyses to identify key structural features of antiviral/antimalarial compounds for their binding interactions with 3CLpro, PLpro and RdRp of SARS-CoV-2: in silico molecular docking and dynamic simulation studies. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2021.1965912

    Article  PubMed  Google Scholar 

  51. de Bruyn Kops C, Stork C, Šícho M, Kochev N, Svozil D, Jeliazkova N, Kirchmair J (2019) GLORY: generator of the structures of likely cytochrome P450 metabolites based on predicted sites of metabolism. Front Chem 7:402

    Article  PubMed  PubMed Central  Google Scholar 

  52. Stork C, Embruch G, Šícho M, de Bruyn Kops C, Chen Y, Svozil D, Kirchmair J (2020) NERDD: a web portal providing access to in silico tools for drug discovery. Bioinformatics 36:1291–1292

    Article  CAS  PubMed  Google Scholar 

  53. de Bruyn Kops C, Šícho M, Mazzolari A, Kirchmair J (2021) GLORYx: prediction of the metabolites resulting from phase 1 and phase 2 biotransformations of xenobiotics. Chem Res Toxicol 34:286–299

    Article  PubMed  Google Scholar 

  54. Chaudhari PJ, Bari SB, Surana SJ, Shirkhedkar AA, Bonde CG, Khadse SC, Ugale VG, Nagar AA, Cheke RS (2022) Discovery and anticancer activity of novel 1,3, 4-thiadiazole-and aziridine-based indolin-2-ones via in silico design followed by supramolecular green synthesis. ACS Omega 7:17270–17294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Dr. P. Narayana Reddy acknowledges the financial support of GITAM University through the GITAM: Research Seed Grants (RSG) (Ref. F. No. 2021/0016). Dr. Pannala Padmaja acknowledges the financial support of Department of Science and Technology (DST) through the Grant WOS-A (No.SR/WOS-A/CS-2/2019). Dr. Vinod G. Ugale acknowledges the financial support from Science and Engineering Research Board (SERB), New Delhi, India (Ref. No. TAR/2021/000140). Dr. Vinod G. Ugale is also thankful to the Principal Dr. S. J. Surana, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra (India) for providing necessary facilities.

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Authors and Affiliations

  1. Department of Chemistry, School of Science, Gitam Deemed to be University, Hyderabad, TS, India

    Visarapu Malathi, Nissi Sharon & Pedavenkatagari Narayana Reddy

  2. Centre for Semio Chemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad, India

    Pannala Padmaja

  3. Rajarshi Shahu College of Pharmacy, Buldana, Maharashtra, India

    Deepak Lokwani

  4. Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, 425405, India

    Saurabh Khadse, Prashant Chaudhari, Atul A. Shirkhedkar & Vinod G. Ugale

  5. Bioprospecting Group, Agharkar Research Institute, Savitribai Phule Pune University, G. G. Agarkar Road, Pune, Maharashtra, 411004, India

    Vinod G. Ugale

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  1. Visarapu Malathi
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Malathi, V., Sharon, N., Padmaja, P. et al. Design, synthesis, and pharmacological evaluation of [1, 3] dioxolo-chromeno[2,3-b]pyridines as anti-seizure agents. Mol Divers 27, 1809–1827 (2023). https://doi.org/10.1007/s11030-022-10538-x

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