Regioselective synthesis and molecular modeling study of vasorelaxant active 7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones

doi:10.1016/j.ejmech.2010.06.018

European Journal of Medicinal Chemistry

Volume 45, Issue 9, September 2010, Pages 4229-4238

https://doi.org/10.1016/j.ejmech.2010.06.018 Get rights and content

Abstract

Nitrilimines (PhC⁻:N⁺:NR′) generated in situ from hydrazonoyl chlorides 2a,b reacted regioselectively with 5-arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones 1a-f to afford 1,3,4-triaryl-8,8-dimethyl-7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones 3a-l. In vitro vasodilation activity screening of the synthesized compounds using isolated thoracic aortic rings of male Wister rats pre-contracted with norepinephrine hydrochloride revealed considerable vasodilation activity; compounds 3f and 3j had IC₅₀ (concentration necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture) of 0.325, 0.321 mM, respectively. Molecular modeling, including fitting to a 3D-pharmacophore model using Discovery studio 2.1 programs and their docking into optimized α₁-AR homology models as α₁-AR antagonist showed high-docking score and fit values. The experimental in vitro vasodilation activity of compounds 3a-l was consistent with the molecular modeling.

Graphical abstract

Introduction

Despite the significant progress in its prevention and treatment, cardiovascular diseases remain the main cause of worldwide mortality, with an increasing number of deaths [1]. Hypertension and atherosclerosis are central to the pathogenesis of coronary artery diseases (ischemia, angina, myocardial infarction), heart failure, cerebral (stroke) and peripheral vascular disease [2]. Therapeutic intervention is the most common therapy to control hypertension and reduce hypertension-related organ damage. Recent progress includes new antihypertensive drugs with three main categories: (1) diuretics and adrenergic receptor blockers; (2) calcium channel blockers and (3) inhibitors targeting the renin-angiotensin system (RAS), namely angiotensin converting enzyme (ACE) inhibitors and angiotensin type-1 (AT₁) receptor antagonists [3]. However, no ideal antiarrhythmic or hypotensive treatment exists without side effects, which include fatigue, mood change, sleep disturbances, dry mouth, blurry vision or impotence. It is urgent to search for new agents with minimal side effects [4].

The present work describes the synthesis of dioxa-diaza-spiro[4.5]decanes by 1,3-dipolar cycloaddition reactions of nitrilimines to [1,3]dioxane-4,6-diones possessing an exocyclic olefinic linkage including regioselectivity. Vasodilation is expansion of blood vessels by relaxation of smooth muscle cells within their walls, especially large and smaller arterioles and large veins. When vessels dilate, the flow of blood is increased due to a decrease in vascular resistance. Therefore, dilation of arterial blood vessels (mainly arterioles) leads to a decrease in blood pressure. This work is a continuation of our investigations in this area searching for bioactive hits easily prepared from accessible starting materials and facile synthetic approaches [5], [6]. Molecular modeling is attempted to validate the observed pharmacological properties and distinguish the obtained structure-activity relationships.

Adrenoceptors (AR) are classified into α-AR and β-AR [7]. α-ARs play a pivotal role in the regulation of a variety of physiological processes, particularly within the cardiovascular system and are divided into two main subtypes α₁- and α₂-ARs [2], [8]. The α₁- and α₂-ARs are located in the vascular smooth muscle cell membrane, and upon stimulation by an appropriate agonist, mediate vasoconstriction. The simultaneous occurrence of both receptor subtypes on vascular smooth muscles indicate that α₁- and α₂-ARs could contribute to the maintenance of peripheral arterial tone and may play an important role in resistance seen in hypertension. α₁-ARs modulate intercellular biochemical processes in response to changes in extracellular concentrations of the neurotransmitter norepinephrine and the circulating hormone epinephrine [9], [10], [11]. Compounds acting as antagonists at various post-junctional α₁-ARs are frequently used in the therapy of high blood pressure, prazosin being the most common drug [8]. α₁-AR antagonists are also used in the treatment of benign prostatic hyperplasia, lower urinary tract symptoms and cardiac arrhythmia [11], [12].

Section snippets

Chemistry

Nitrilimines (PhC⁻:N⁺:NR′) generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides 2a,b using triethylamine underwent 1,3-dipolar cycloadditions with various 5-arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones 1a-f under reflux in benzene to afford single products (TLC). The isolated products were established to be 1,3,4-triaryl-8,8-dimethyl-7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones 3a-l rather than their regio-isomers

Conclusion

In conclusion, 1,3-dipolar cycloaddition reaction of nitrilimines with 5-arylidene[1,3]dioxane-4,6-diones 1 proceeds highly regioselectively affording 7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones 3 in good yields (60–79% yield). The constructed heterocycles possess good vasorelaxant properties as exhibited during in vitro activity screening using thoracic aortic rings of male Wister rats pre-contracted with norepinephrine hydrochloride according to the standard reported procedure.

Experimental

Melting points were recorded on a Stuart SMP3 digital melting point apparatus. IR spectra (KBr) were recorded on a JASCO 6100 FT-IR spectrophotometer. NMR spectra were recorded on a Varian MERCURY 300 (¹H: 300; ¹³C: 75 MHz) spectrometer. The starting compounds 1a-f [26], [27], [28], [29], [30] and 2a,b [31], [32] were prepared according to the previously reported procedures.

Acknowledgment

This work is sponsored by the U.S. – Egypt Science and Technology Joint Fund under project No. MAN10-007-002.

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Original articleRegioselective synthesis and molecular modeling study of vasorelaxant active 7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

Experimental

Acknowledgment

Lancet

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Pharmacol. Ther.

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

Tetrahedron

Eur. J. Pharmacol.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

J. Mol. Graph. Model.

Original article
Regioselective synthesis and molecular modeling study of vasorelaxant active 7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones