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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, and Smail Khelili

Laboratory of Phytochemistry and Pharmacology, Department of Chemistry, Faculty of Exact Sciences and Informatics, University of Mohamed Seddik Ben Yahia Jijel, Jijel, Algeria

 

E-mail: skhelili@yahoo.fr

Received: 24 February 2019  Accepted: 5 September 2019

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

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-019-00925-4

 

Chemical Papers 74 (3) 915–928 (2020)

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