Advertisement

Synthesis and vasodilator activity of new 1,4-dihyropyridines bearing sulfonylurea, urea and thiourea moieties

  • Mohamed Zakaria Stiti
  • Mebrouk Belghobsi
  • Tahir Habila
  • Eric Goffin
  • Pascal de Tullio
  • Bernard Pirotte
  • Gilles Faury
  • Smail KheliliEmail author
Original Paper
  • 12 Downloads

Abstract

Some new 1,4-dihydropyridines bearing sulfonylurea, urea and thiourea moieties were synthesized and pharmacologically evaluated for their vasodilator activity, comparatively to nifedipine and diazoxide. The investigations of the target compounds on rat aorta rings showed that, except the sulfonylureas derivatives, which were inactive (EC50 > 100 μΜ), ureas and thioureas derivatives showed moderate to strong vasodilator activity, with EC50 values varying from 1.2 to 40 μM. 17-fold more active than diazoxide (but less active than nifedipine), the most active compound (1.2 ± 0.2 μM) was found to be a voltage-gated calcium channels blocker, as it is the case for the reference compound, nifedipine. The results also showed that an aliphatic or aromatic R group (the latter bearing electro-donating or electro-withdrawing substituents) gave very active compounds. The inactiveness of sulfonylurea derivatives could be explained by a partial ionization at physiological pH because of their weak acid character. Finally, it would be very suitable to synthesize N-methylated analogs of sulfonylurea derivatives, and more urea and thiourea derivatives bearing aliphatic R groups, and to test them on the same pharmacological model. Therefore, the series of 1,4-dihydropyridines described herein displayed good potential for the development of new vasodilator agents in the search for new therapeutics for the treatment of some cardiovascular diseases.

Graphic abstract

Keywords

1,4-dihydropyridine Urea Thiourea Sulfonylurea Vasodilator activity Voltage-gated calcium channel blockers 

Notes

Acknowledgements

This work was supported by the Algerian Ministry of Higher Education and Scientific Research, Laboratory of Phytochemistry and Pharmacology (University of Mohamed Seddik Ben Yahia, Jijel-Algeria), Laboratory of Pharmaceutical chemistry (University of Liège-Belgium), and HP2 Laboratory (University of Grenoble-Alpes, France). The authors gratefully acknowledge the technical assistance of Stéphane Counerotte, Sandrine Cachot, Bouraoui Hadia and Aibech Riad.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

11696_2019_925_MOESM1_ESM.docx (2.9 mb)
Supplementary material 1 (DOCX 2954 kb)

References

  1. Ahamed A, Arif IA, Mateen M, Kumar RS, Idhayadhulla A (2018) Antimicrobial, anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4-dihydropyridine derivatives. Saudi J Biol Sci 25:1227–1235.  https://doi.org/10.1016/j.sjbs.2018.03.001 CrossRefGoogle Scholar
  2. Alker D, Campbell SF, Cross PE, Burges RA, Carter AJ, Gardiner DG (1990) Long-acting dihydropyridine calcium antagonists. 4. Synthesis and structure-activity relationships for a series of basic and non-basic derivatives of 2 [(2-aminoethoxy) methyl]-1,4-dihydropyridine calcium antagonists. J Med Chem 33:585–591.  https://doi.org/10.1021/jm00164a019 CrossRefGoogle Scholar
  3. Angelico P, Guarneri L, Leonardi A, Testa R (1999) Vascular-selective effect of lercanidipine and other 1,4-dihydropyridines in isolated rabbit tissues. J Pharm Pharmacol 51:709–714.  https://doi.org/10.1211/0022357991772844 CrossRefGoogle Scholar
  4. Barbosa FA, Canto RF, Saba S, Rafique J, Braga AL (2016) Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer’s disease. Bioorg Med Chem 24:5762–5770.  https://doi.org/10.1016/j.bmc.2016.09.031 CrossRefGoogle Scholar
  5. Bouhedja M, Peres B, Fhayli W, Ghandour Z, Boumendjel A, Faury G, Khelili S (2018) Design, synthesis and biological evaluation of novel ring-opened cromakalim analogues with relaxant effects on vascular and respiratory smooth muscles and as stimulators of elastin synthesis. Eur J Med Chem 144:774–796.  https://doi.org/10.1016/j.ejmech.2017.12.071 CrossRefGoogle Scholar
  6. Bouider N et al (2015) Design and synthesis of new potassium channel activators derived from the ring opening of diazoxide: study of their vasodilatory effect, stimulation of elastin synthesis and inhibitory effect on insulin release. Bioorg Med Chem 23:1735–1746.  https://doi.org/10.1016/j.bmc.2015.02.043 CrossRefGoogle Scholar
  7. Canto RF, Barbosa FA, Nascimento V, de Oliveira AS, Brighente IM, Braga AL (2014) Design, synthesis and evaluation of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer’s disease. Org Biomol Chem 12:3470–3477.  https://doi.org/10.1039/c4ob00598h CrossRefGoogle Scholar
  8. Carosati E, Budriesi R, Ioan P, Ugenti MP, Frosini M, Fusi F, Corda G, Cosimelli B, Spinelli D, Chiarini A (2008) Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening. J Med Chem 51:5552–5565.  https://doi.org/10.1021/jm800151n CrossRefGoogle Scholar
  9. Cominacini L, Pasini AF, Garbin U, Pastorino AM, Davoli A, Nava C, Campagnola M, Rossato P, Cascio VL (2003) Antioxidant activity of different dihydropyridines. Biochem Biophys Res Commun 302:679–684.  https://doi.org/10.1016/S0006-291X(03)00158-X CrossRefGoogle Scholar
  10. da Cabrera DC, Santa-Helena E, Leal HP, de Moura RR, Nery LEM, Gonçalves CAN, Russowsky D, D’Oca MGM (2019) Synthesis and antioxidant activity of new lipophilic dihydropyridines. Bioorg Chem 84:1–16.  https://doi.org/10.1016/j.bioorg.2018.11.009 CrossRefGoogle Scholar
  11. Dehpour AR, Samini M, Rastegar H, Delfan A, Ghafourifar P (1994) Comparison of various calcium channel blockers on guinea-pig isolated common bile duct. Gen Pharmacol 25:1655–1660.  https://doi.org/10.1016/0306-3623(94)90368-9 CrossRefGoogle Scholar
  12. Desai NC, Trivedi AR, Somani HC, Bhatt KA (2015) Design, synthesis, and biological evaluation of 1,4-dihydropyridine derivatives as potent antitubercular agents. Chem Biol Drug Des 86:370–377.  https://doi.org/10.1111/cbdd.12502 CrossRefGoogle Scholar
  13. Goldmann S, Stoltefuss J (1991) 1, 4-Dihydropyridines: effects of chirality and conformation on the calcium antagonist and calcium agonist activities. Angew Chem Int Ed 30:1559–1578.  https://doi.org/10.1002/anie.199115591 CrossRefGoogle Scholar
  14. Habila T, Belghobsi M, Stiti M-Z, Goffin E, de Tullio P, Faury G, Pirotte B, Khelili S (2019) Synthesis and vasodilator activity of 3,4-dihydropyrimidin-2(1H)-ones bearing urea, thiourea, and sulfonylurea moieties. Can J Chem 97:20–28.  https://doi.org/10.1139/cjc-2018-0239 CrossRefGoogle Scholar
  15. Harrouche K, Renard J-F, Bouider N, De Tullio P, Goffin E, Lebrun P, Faury G, Pirotte B, Khelili S (2016) Synthesis, characterization and biological evaluation of benzothiazoles and tetrahydrobenzothiazoles bearing urea or thiourea moieties as vasorelaxants and inhibitors of the insulin releasing process. Eur J Med Chem 115:352–360.  https://doi.org/10.1016/j.ejmech.2016.03.028 CrossRefGoogle Scholar
  16. Hayashi K, Kumagai H, Saruta T (2003) Effect of efonidipine and ACE inhibitors on proteinuria in human hypertension with renal impairment. Am J Hypertens 16:116–122.  https://doi.org/10.1016/S0895-7061(02)03147-3 CrossRefGoogle Scholar
  17. Hilgeroth A (2002) Dimeric 4-Aryl-1,4-dihydropyridines: development of a third class of nonpeptidic HIV-1 protease inhibitors. Mini Rev Med Chem 2:235–245.  https://doi.org/10.2174/1389557023406241 CrossRefGoogle Scholar
  18. Hoshide S, Kario K, Mitsuhashi T, Ikeda U, Shimada K (2000) Is there any difference between intermediate-acting and long-acting calcium antagonists in diurnal blood pressure and autonomic nervous activity in hypertensive coronary artery disease patients. Hypertens Res 23:7–14.  https://doi.org/10.1291/hypres.23.7 CrossRefGoogle Scholar
  19. Hosseini ZS, Housaindokht MR, Razzaghi-Asl N, Miri R (2018) Virtual screening of some heterocyclic structures toward novel antibacterial agents. J Iran Chem Soc 15:621–628.  https://doi.org/10.1007/s13738-017-1262-2 CrossRefGoogle Scholar
  20. Inayoshi A, Sugimoto Y, Funahashi J, Takahashi S, Matsubara M, Kusaka H (2011) Mechanism underlying the block of human Cav3. 2 T-type Ca2+ channels by benidipine, a dihydropyridine Ca2+ channel blocker. Life Sci 88:898–907.  https://doi.org/10.1016/j.lfs.2011.03.019 CrossRefGoogle Scholar
  21. Janis RA, Triggle D (1983) New developments in calcium ion channel antagonists. J Med Chem 26:775–785.  https://doi.org/10.1021/jm00360a001 CrossRefGoogle Scholar
  22. Jetti SR, Upadhyaya A, Jain S (2014) 3, 4-Hydropyrimidin-2-(1H) one derivatives: solid silica-based sulfonic acid catalyzed microwave-assisted synthesis and their biological evaluation as antihypertensive and calcium channel blocking agents. Med Chem Res 23:4356–4366.  https://doi.org/10.1007/s00044-014-0988-y CrossRefGoogle Scholar
  23. Kappe CO (2000) Biologically active dihydropyrimidones of the Biginelli-type-a literature survey. Eur J Med Chem 35:1043–1052.  https://doi.org/10.1016/S0223-5234(00)01189-2 CrossRefGoogle Scholar
  24. Khelili S, Kihal N, Yekhlef M, De Tullio P, Lebrun P, Pirotte B (2012) Synthesis and pharmacological activity of N-(2, 2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-4H-1,2,4-benzothiadiazine-3-carboxamides 1, 1-dioxides on rat uterus, rat aorta and rat pancreatic β-cells. Eur J Med Chem 54:873–878.  https://doi.org/10.1016/j.ejmech.2012.05.011 CrossRefGoogle Scholar
  25. Khoshneviszadeh M, Edraki N, Javidnia K, Alborzi A, Pourabbas B, Mardaneh J, Miri R (2009) Synthesis and biological evaluation of some new 1,4-dihydropyridines containing different ester substitute and diethyl carbamoyl group as anti-tubercular agents. Bioorg Med Chem 17:1579–1586.  https://doi.org/10.1016/j.bmc.2008.12.070 CrossRefGoogle Scholar
  26. Kosaka H, Hirayama K, Yoda N, Sasaki K, Kitayama T, Kusaka H, Matsubara M (2010) The L-, N-, and T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family. Eur J Pharmacol 635:49–55.  https://doi.org/10.1016/j.ejphar.2010.03.018 CrossRefGoogle Scholar
  27. Kumar SR, Idhayadhulla A, Nasser AJA, Selvin J (2011) Synthesis and antimicrobial activity of a new series 1,4-dihydropyridine derivatives. J Serb Chem Soc 76:1–11.  https://doi.org/10.2298/JSC091127003K CrossRefGoogle Scholar
  28. Lebrun P, Becker B, Morel N, Ghisdal P, Antoine M-H, De Tullio P, Pirotte B (2008) KATP channel openers: tissue selectivity of original 3-alkylaminopyrido-and 3-alkylaminobenzothiadiazine 1,1-dioxides. Biochem Pharmacol 75:468–475.  https://doi.org/10.1016/j.bcp.2007.08.032 CrossRefGoogle Scholar
  29. Marco-Contelles J, León R, de los Ríos C, Guglietta A, Terencio J, López MG, García AG, Villarroya M (2006) Novel multipotent tacrine−dihydropyridine hybrids with improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of Alzheimer’s disease. J Med Chem 49:7607–7610.  https://doi.org/10.1021/jm061047j CrossRefGoogle Scholar
  30. Mehanna AS, Kim JY (2005) Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers. Bioorg Med Chem 13:4323–4331.  https://doi.org/10.1016/j.bmc.2005.04.012 CrossRefGoogle Scholar
  31. Mohareb RM, Ibrahim RA, Wardakhan WW (2016) Synthesis of pyridine, pyran and thiazole containing thiophene derivatives and their antitumor evaluations. Med Chem Res 25:2187–2204.  https://doi.org/10.1007/s00044-016-1654-3 CrossRefGoogle Scholar
  32. Murthy Y, Rajack A, Ramji MT, Praveen C, Lakshmi KA (2012) Design, solvent free synthesis, and antimicrobial evaluation of 1,4dihydropyridines. Bioorg Med Chem Lett 22:6016–6023.  https://doi.org/10.1016/j.bmcl.2012.05.003 CrossRefGoogle Scholar
  33. Ogihara T, Matsuzaki M, Matsuoka H, Shimamoto K, Shimada K, Rakugi H, Umemoto S, Kamiya A, Suzuki N, Kumagai H (2005) The combination therapy of hypertension to prevent cardiovascular events (COPE) trial. Hypertens Res 28:331.  https://doi.org/10.1291/hypres.28.331 CrossRefGoogle Scholar
  34. Patil AD, Kumar NV, Kokke WC, Bean MF, Freyer AJ, Brosse CD, Mai S, Truneh A, Carte B (1995) Novel alkaloids from the sponge Batzella sp.: inhibitors of HIV gp120-human CD4 binding. J Org Chem 60:1182–1188.  https://doi.org/10.1021/jo00110a021 CrossRefGoogle Scholar
  35. Pirotte B, De Tullio P, Florence X, Goffin E, Somers F, Sp Boverie, Lebrun P (2013) 1, 4, 2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the atp-sensitive potassium channel openers 1,2,4-benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action. J Med Chem 56:3247–3256.  https://doi.org/10.1021/jm301743b CrossRefGoogle Scholar
  36. Rekunge DS, Khatri CK, Chaturbhuj GU (2017) Sulfated polyborate: an efficient and reusable catalyst for one pot synthesis of Hantzsch 1,4-dihydropyridines derivatives using ammonium carbonate under solvent free conditions. Tetrahedron Lett 58:1240–1244.  https://doi.org/10.1016/j.tetlet.2017.02.038 CrossRefGoogle Scholar
  37. Singh B (1986) The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol 21:109S–121S.  https://doi.org/10.1111/j.1365-2125.1986.tb02860.x CrossRefGoogle Scholar
  38. Sirisha K, Bikshapathi D, Achaiah G, Reddy VM (2011) Synthesis, antibacterial and antimycobacterial activities of some new 4-aryl/heteroaryl-2,6-dimethyl-3, 5-bis-N-(aryl)-carbamoyl-1, 4-dihydropyridines. Eur J Med Chem 46:1564–1571.  https://doi.org/10.1016/j.ejmech.2011.02.003 CrossRefGoogle Scholar
  39. Somers F, Ouedraogo R, Antoine M-H, De Tullio P, Becker B, Fontaine J, Damas J, Dupont L, Rigo B, Delarge J (2001) Original 2-alkylamino-6-halogenoquinazolin-4 (3H)-ones and KATP channel activity. J Med Chem 44:2575–2585.  https://doi.org/10.1021/jm0004648 CrossRefGoogle Scholar
  40. Tawfik HA, Bassyouni F, Gamal-Eldeen AM, Abo-Zeid MA, El-Hamouly WS (2009) Tumor anti-initiating activity of some novel 3,4-dihydropyrimidinones. Pharmacol Rep 61:1153–1162.  https://doi.org/10.1016/S1734-1140(09)70178-1 CrossRefGoogle Scholar
  41. Verdecia Y, Suárez M, Morales A, Rodríguez E, Ochoa E, González L, Martín N, Quinteiro M, Seoane C, Soto JL (1996) Synthesis of methyl 4-aryl-6-methyl-4,7-dihydro-1H-pyrazolo-[3,4-b]pyridine-5-carboxylates from methyl4-aryl-6-methyl-2-oxo-1,2,3,4-tetrahydropyridine-5-carboxylates. J Chem Soc Perkin Trans 1:947–951.  https://doi.org/10.1039/p19960000947 CrossRefGoogle Scholar
  42. Vijesh A, Isloor AM, Peethambar S, Shivananda K, Arulmoli T, Isloor NA (2011) Hantzsch reaction: synthesis and characterization of some new 1, 4-dihydropyridine derivatives as potent antimicrobial and antioxidant agents. Eur J Med Chem 46:5591–5597.  https://doi.org/10.1016/j.ejmech.2011.09.026 CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2019

Authors and Affiliations

  1. 1.Laboratory of Phytochemistry and Pharmacology, Department of Chemistry, Faculty of Exact Sciences and InformaticsUniversity of Mohamed Seddik Ben Yahia JijelJijelAlgeria
  2. 2.Laboratory of Pharmaceutical Chemistry, Center for Interdisciplinary Research on Medicines (CIRM)University of LiegeLiègeBelgium
  3. 3.Laboratory of ‘Hypoxy: Cardiovascular and Respiratory Physiopathology’ (HP2)INSERM U1042-University of Grenoble-AlpesLa TroncheFrance

Personalised recommendations