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Synthesis, pharmacological evaluation and molecular docking of pyranopyrazole-linked 1,4-dihydropyridines as potent positive inotropes

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Abstract

1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification.

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References

  1. Carafoli E, Klee C (1999) Calcium as cellular regulator. Oxford University Press, New York, pp 171–200

    Google Scholar 

  2. William JE, Venkata CSR (2011) Calcium channel blockers. J Clin Hypertens 13:687–689. doi:10.1111/j.1751-7176.2011.00513

    Article  Google Scholar 

  3. Bossert F, Meyer H, Wehinger E (1981) 4-Aryldihydropyridines, a new class of highly active calcium antagonists. Angew Chem Int Edit 20:762–769. doi:10.1002/anie.198107621

    Article  Google Scholar 

  4. Sohal HS, Goyal A, Sharma R, Khare R (2014) One-pot multicomponent synthesis of symmetrical Hantzsch 1,4-dihydropyridine derivatives using glycerol as clean and green solvent. Eur J Med Chem 5:171–175. doi:10.5155/eurjchem.5.1.171-175.943

    Article  Google Scholar 

  5. Ali HI, Ashida N, Nagamatsu T (2007) Design, synthesis, antitumor activity, and molecular docking study of novel 2-methylthio-, 2-amino-, and 2-(\(N\)-substituted amino)-10-alkyl-2-deoxo-5-deazaflavins. Bioorg Med Chem 15:6336–6352. doi:10.1016/j.bmc.2007.06.058

    Article  CAS  PubMed  Google Scholar 

  6. Pavani MG, Nunez M, Brigidi P, Vitali B, Gambari R (2002) Antimicrobial and antitumor activity of \(N\)-heteroimmine-1,2,3-dithiazoles and their transformation in triazolo-, imidazo-, and pyrazolopirimidines. Bioorg Med Chem 10:449–456. doi:10.1016/S0968-0896(01)00294-2

    Article  PubMed  Google Scholar 

  7. Sondhi SM, Johar M, Rajvanshi S, Dastidar SG, Shukla R, Raghubir R, Lown JW (2001) Anticancer, anti-inflammatory and analgesic activity evaluation of heterocyclic compounds synthesized by the reaction of 4-isothiocyanato-4-methylpentan-2-one with substituted \(o\)-phenylenediamines, \(o\)-diaminopyridine and (Un)substituted. Aust J Chem 54:69–74. doi:10.1071/CH00141

    Article  CAS  Google Scholar 

  8. Narayana LB, Rao RRA, Rao SP (2009) Synthesis of new 2-substituted pyrido[2,3-\(d\)]pyrimidin-4(1H)-ones and their antibacterial activity. Eur J Med Chem 44:1369–1376. doi:10.1016/j.ejmech.2008.05.025

    Article  Google Scholar 

  9. Trivedi A, Dodiya D, Dholariya B, Kataria V, Bhuva V, Shah V (2011) Synthesis and biological evaluation of some novel 1,4-dihydropyridines as potential antitubercular agents. Chem Biol Drug Des 78:881–886. doi:10.1111/j.1747-0285.2011.01233.x

    Article  CAS  PubMed  Google Scholar 

  10. Shishoo CJ, Shirsath VS, Rathod IS, Patil MJ, Bhargava SS (2001) Design, synthesis and antihistaminic (H1) activity of some condensed 2-(substituted) arylaminoethylpyrimidine-4-(3\(H\))-ones. Arzneim Forsch 51:221–231

    CAS  Google Scholar 

  11. Jiang J, Rhee MA, Melman N, Ji X, Jacobson KA (2006) 6-Phenyl-1,4-dihydropyridine derivatives as potent and selective A3 adenosine receptor antagonists. J Med Chem 39:4667–4675. doi:10.1021/jm960457c

    Article  Google Scholar 

  12. Li AH, Chang L, Ji X, Melman N, Jacobson KA (2009) Functionalized congeners of 1,4-dihydropyridines as antagonist molecular probes for A3 adenosine receptors. Bioconjug Chem 10:667–677. doi:10.1021/bc9900136

    Article  Google Scholar 

  13. Bakali JE, Gilleron P, Malapel MB, Mansouri R, Muccioli GG, Djouina M, Barczyk A, Klupsch F, Andrzejak V, Lipka E, Furman C, Lambert DM, Chavatte P, Desreumaux P, Millet R (2012) 4-Oxo-1,4-dihydropyridines as selective CB2 cannabinoid receptor ligands. Part 2: Discovery of new agonists endowed with protective effect against experimental colitis. J Med Chem 55:8948–8952. doi:10.1021/jm3008568

    Article  PubMed  Google Scholar 

  14. Nantermet PG, Barrow JC, Selnick HG, Homnick CF, Freidinger RM, Chang RS, O’Malley SS, Reiss DR, Broten TP, Ransom RW, Pettibone DJ, Olah T, Forray C (2000) Selective \(\upalpha \)1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones. Bioorg Med Chem Lett 10:1625–1628. doi:10.1016/S0960-894X(99)00696-4

    Article  CAS  PubMed  Google Scholar 

  15. Niwa T, Shiraga T, Hashimoto T, Kagayama A (2004) Effect of Nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes. Biol Pharm Bull 27:415–417. doi:10.1248/bpb.27.415

    Article  CAS  PubMed  Google Scholar 

  16. Viegas-Junior C, Danuello A, Silva DBV, Barreiro EJ, Fraga CA (2007) Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem 14:1829–1829. doi:10.2174/092986707781058805

    Article  CAS  PubMed  Google Scholar 

  17. Huang LJ, Hour MJ, Teng CM, Kuo SC (1992) Synthesis and antiplatelet activities of \(N\)-arylmethyl-3,4-dimethylpyrano[2,3-\(c\)]pyrazol-6-one derivatives. Chem Pharm Bull 40:2547–2551

    Article  CAS  PubMed  Google Scholar 

  18. Mohamed NR, Khaireldin NY, Fahmyb AF, El-Sayeda AAF (2010) Facile synthesis of fused nitrogen containing heterocycles as anticancer agents. Der Pharm Chem 2:400–417

    CAS  Google Scholar 

  19. Ueda T, Mase H, Oda N, Ito I (1981) Synthesis of pyrazolone derivatives. XXXIX. Synthesis and analgesic activity of pyrano[2,3-\(c\)]pyrazoles. Chem Pharm Bull 29:3522–3528. doi:10.1248/cpb.29.3522

    Article  CAS  PubMed  Google Scholar 

  20. Kuo SC, Huang LJ, Nakamura H (1984) Synthesis and analgesic and antiinflammatory activities of 3,4-dimethylpyrano[2,3-\(c\)]pyrazol-6-one derivatives. J Med Chem 27:539–544. doi:10.1021/jm00370a020

    Article  CAS  PubMed  Google Scholar 

  21. Assiery SE, Sayed GH, Fouda A (2004) Synthesis of some new annulated pyrazolo-pyrido (or pyrano) pyrimidine, pyrazolopyridine and pyranopyrazole derivatives. Acta Pharma 54:143–150

    Google Scholar 

  22. Mohammad MM, Mohammad RJ, Mohammad B (2006) Facile synthesis of pyrano[2,3-\(c\)]pyrazol-6-one derivatives under microwave irradiation in solvent-free conditions. Synth Comm 36:51–58. doi:10.1080/00397910500328886

    Article  Google Scholar 

  23. Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayama H, Kanaoka Y, Minamino N (1984) Primary structure of electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312:121–127. doi:10.1038/312121a0

    Article  CAS  Google Scholar 

  24. Tanabe T, Takeshima H, Mikami A, Flockerzi V, Takahashi H, Kanqawa A, Kojima M, Matsuo H, Hirose T, Numa S (1987) Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature 328:313–318. doi:10.1038/328313a0

    Article  CAS  Google Scholar 

  25. Tempel BL, Papazian DM, Schwarz TL, Jan LY, Jan YN (1987) Sequence of a probable potassium channel component encoded at Shaker locus of Drosophila. Science 237:770–775. doi:10.1126/science.2441471

    Article  CAS  PubMed  Google Scholar 

  26. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749. doi:10.1021/jm0306430

    Article  CAS  PubMed  Google Scholar 

  27. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47(7):1750–1759. doi:10.1021/jm030644s

    Article  CAS  PubMed  Google Scholar 

  28. Halgren TA (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49(2):377–389. doi:10.1021/ci800324m

    Article  CAS  PubMed  Google Scholar 

  29. Tikhonov DB, Zhorov BS (2005) Modeling P-loops domain of sodium channel: homology with potassium channels and interaction with ligands. Biophys J 88:184–197. doi:10.1529/biophysj.104.048173

    Article  CAS  PubMed  Google Scholar 

  30. Tikhonov DB, Zhorov BS (2008) Molecular modeling of benzothiazepine binding in the L-type calcium channel. J Biol Chem 283:17594–17604. doi:10.1074/jbc.M800141200

    Article  CAS  PubMed  Google Scholar 

  31. Yamaguchi S, Zhorov BS, Yoshioka K, Nagao T, Ichijo H, Adachi-Akahane S (2003) Key roles of Phe1112 and Ser1115 in the pore-forming IIIS5–S6 linker of L-type Ca\(^{2+}\) channel alpha1C subunit (CaV 1.2) in binding of dihydropyridines and action of Ca\(^{2+}\) channel agonists. Mol Pharmacol 64:235–248. doi:10.1124/mol.64.2.235

    Article  CAS  PubMed  Google Scholar 

  32. Vidal D, Garcia-Serna R, Mestres J (2011) Ligand-based approaches to in silico pharmacology. Methods Mol Biol 672:489–502. doi:10.1007/978-1-60761-839-3_19

    Article  CAS  PubMed  Google Scholar 

  33. Garcia-Serna R, Vidal D, Remez N, Mestres J (2015) Large-scale predictive drug safety: from structural alerts to biological mechanisms. Chem Res Toxicol 28:1875–1887. doi:10.1021/acs.chemrestox.5b00260

    Article  CAS  PubMed  Google Scholar 

  34. Gaulton A, Hersey A, Nowotka M, Bento AP, Chambers J, Mendez D, Mutowo P, Atkinson F, Bellis LJ, Cibrián-Uhalte E, Davies M, Dedman N, Karlsson A, Magariños MP, Overington JP, Papadatos G, Smit I, Leach AR (2017) The ChEMBL database in 2017. Nucleic Acids Res 45:D945–D954. doi:10.1093/nar/gkw1074

    Article  PubMed  Google Scholar 

  35. Matsui T, Takeuchi M, Yamagishi S (2010) Nifedipine, a calcium channel blocker, inhibits inflammatory and fibrogenic gene expressions in advanced glycation end product (AGE)-exposed fibroblasts via mineralocorticoid receptor antagonistic activity. Biochem Biophys Res Commun 396:566–570. doi:10.1016/j.bbrc.2010.04.149

    Article  CAS  PubMed  Google Scholar 

  36. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236. doi:10.1021/ja9621760

    Article  CAS  Google Scholar 

  37. SiteMap (2009) version 2.3, Schrödinger. LLC, New York, NY

  38. Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK (2007) Relating protein pharmacology by ligand chemistry. Nat Biotechnol 25:197–206. doi:10.1038/nbt1284

    Article  CAS  PubMed  Google Scholar 

  39. Briansó F, Carrascosa MC, Oprea TI, Mestres J (2011) Cross-pharmacology analysis of G protein-coupled receptors. Curr Top Med Chem 11:1956–1963. doi:10.2174/156802611796391285

  40. Areias FM, Brea J, Gregori-Puigjané E, Zaki MEA, Carvalho MA, Domínguez E, Gutiérrez-de-Terán H, Proença MF, Loza MI, Mestres J (2010) In silico directed chemical probing of the adenosine receptor family. Bioorg Med Chem 18:3043–3052. doi:10.1016/j.bmc.2010.03.048

    Article  CAS  PubMed  Google Scholar 

  41. Mestres J, Seifert SA, Oprea TI (2011) Linking pharmacology to clinical reports: cyclobenzaprine and its possible association with serotonin syndrome. Clin Pharmacol Ther 90:662–665. doi:10.1038/clpt.2011.177

    Article  CAS  PubMed  Google Scholar 

  42. Antolín AA, Jalencas X, Yélamos J, Mestres J (2012) Identification of PIM kinases as novel targets for PJ34 with confounding effects in PARP biology. ACS Chem Biol 7:1962–1967. doi:10.1021/cb300317y

    Article  PubMed  Google Scholar 

  43. Antolín AA, Mestres J (2015) Distant polypharmacology among MLP chemical probes. ACS Chem Biol 10:395–400. doi:10.1021/cb500393m

    Article  PubMed  Google Scholar 

  44. Montolio M, Gregori-Puigjané E, Pineda D, Mestres J, Navarro P (2012) Identification of small molecule inhibitors of amyloid \(\upbeta \)-induced neuronal apoptosis acting through the imidazoline I(2) receptor. J Med Chem 55:9838–9846. doi:10.1021/jm301055g

    Article  CAS  PubMed  Google Scholar 

  45. Waller CL, Juma BW, Gray LE Jr, Kelce WR (1996) Three-dimensional quantitative structure-activity relationships for androgen receptor ligands. Toxicol Appl Pharmacol 137:219–227. doi:10.1006/taap.1996.0075

    Article  CAS  PubMed  Google Scholar 

  46. Stefanachi A, Nicolotti O, Leonetti F, Cellamare S, Campagna F, Loza MI, Brea JM, Mazza F, Gavuzzo E, Carotti A (2008) 1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines as potent A2B adenosine receptor antagonists: design, synthesis, structure-affinity and structure-selectivity relationships. Bioorg Med Chem 16:9780–9789. doi:10.1016/j.bmc.2008.09.067

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was partially supported by ChemBiobank, the Chemical Biology infrastructure initiative in Spain, carrying out the predictive and the biological activity of the synthesized compounds. The authors would like to thank CDRI, Lucknow, for carrying out the in vivo studies, Defence Research and Development Organization (DRDO) for financial support and University of Delhi, Delhi, for providing the laboratory and instrumentation facility.

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Authors and Affiliations

  1. Bio-organic Laboratory, Department of Chemistry, University of Delhi, Delhi, 110 007, India

    Rakesh Kumar, Neha Yadav, Mamta Bhandari, Ritu Arora, Rita Kakkar & Ashok K. Prasad

  2. Laboratory of Organic Chemistry, Department of Pharmacology and Therapeutical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain

    Rodolfo Lavilla

  3. Drug Discovery Platform, Parc Científic de Barcelona, Baldiri Reixac 10-12, 08028, Barcelona, Spain

    Daniel Blasi & Jordi Quintana

  4. USEF Screening Platform, Centre of Research on Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain

    José Manuel Brea & María Isabel Loza

  5. Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute and University Pompeu Fabra, Doctor Aiguader 88 (PRBB), 08003, Barcelona, Catalonia, Spain

    Jordi Mestres

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  1. Rakesh Kumar
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Correspondence to Rakesh Kumar.

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11030_2017_9738_MOESM1_ESM.docx

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Kumar, R., Yadav, N., Lavilla, R. et al. Synthesis, pharmacological evaluation and molecular docking of pyranopyrazole-linked 1,4-dihydropyridines as potent positive inotropes. Mol Divers 21, 533–546 (2017). https://doi.org/10.1007/s11030-017-9738-7

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