Synthesis and vasodilator activity of new 1,4-dihyropyridines bearing sulfonylurea, urea and thiourea moieties
- 12 Downloads
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.
Keywords1,4-dihydropyridine Urea Thiourea Sulfonylurea Vasodilator activity Voltage-gated calcium channel blockers
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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