Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives

doi:10.1016/j.ejmech.2009.04.044

European Journal of Medicinal Chemistry

Volume 44, Issue 10, October 2009, Pages 4004-4009

https://doi.org/10.1016/j.ejmech.2009.04.044 Get rights and content

Abstract

In this report we disclose the synthesis, vasodilatory activity, and identification of bioactive conformation of new N-acylhydrazone and N-methyl-N-acylhydrazone derivatives, structurally designed by bioisosteric replacements of previously described cardioactive compounds LASSBio-294 and its N-methyl derivative LASSBio-785. Some of these novel derivatives presented improved vasorelaxant properties, being new cardiovascular drug candidates.

Graphical abstract

In this paper is described the bioactive conformation of new N-acylhydrazone (NAH) derivatives, bioisostere of the previously described potent cardioactive compound LASSBio-294. These novel derivatives – N-methyl homologues – presented important vasodilator properties.

Introduction

Hypertension is the most common cardiovascular disease, and the one which represents the major risk factor for coronary artery disease, heart failure, stroke and renal failure [1]. The reduction in blood pressure achieved with most of the currently used antihypertensive agents, such as angiotensin-converting enzyme inhibitors, calcium antagonists, β-blockers and diuretics, is direct or indirectly related to the relaxation of the vascular smooth muscle [2]. Several direct vasodilators have been synthesized but none of them has presented a specific action while being free of side effects, reinforcing the importance of identifying new clinically safe useful vasodilator agents [3].

The strategy of molecular simplification on pyridazinone phosphodiesterase (PDE) inhibitors (1) [4], represented by a simple bond rupture in a and the elimination of the stereogenic center in b, enabled us to recognize the structural similarity between N-acylhydrazone (NAH) derivatives (2) and these cardioactive compounds [5]. The inclusion of the 1,3-benzodioxolyl ring, coming from Brazilian natural safrole (3) [6] attached to the acyl group of NAH moiety [7], [8] and replacing the phenyl ring attached to the imine moiety by the bioisosteric 2-thienyl ring [9] resulted in the design of 3,4-methylenedioxybenzoyl-2-thienyl-hydrazone, named LASSBio-294 (4) (Chart 1) [5].

LASSBio-294 (4) was described as a potent positive cardio-inotropic agent due to an increase in the Ca²⁺ accumulation in the sarcoplasmic reticulum (SR) [10]. In addition, LASSBio-294 (4) also promoted vasodilation in aortic rings, mediated by the guanylate cyclase/cyclic guanylate monophosphate pathway [11].

Considering that the N-acylhydrazone subunit present in LASSBio-294 (4) has an isosteric relationship with the pyridazinone ring shared by phosphodiesterase (PDE) inhibitors [12], the bioprofiles of several synthetic analogues planned by structural optimization of the lead compound LASSBio-294 (4) were investigated in the vascular smooth muscle [13]. Among the derivatives tested on the contractile response of the vascular smooth muscle of Wistar rats, we observed that changes in electronic density of the thienyl subunit did not increase the vasodilatory effects [13]. However, the introduction of small alkyl groups linked to the amide nitrogen of the NAH moiety of LASSBio-294 (4), especially the methyl group, led to the discovery of derivative LASSBio-785 (5), which presented a significant improvement in vasodilator properties (IC₅₀ was 10.2 ± 0.5 μM), being seven times more potent than LASSBio-294 (4) in the same bioassay [13].

Herein we explore the synthesis of new arylidene N-acylhydrazones (6a–c) and their corresponding N-methyl derivatives (9a–c) planned by classical bioisosteric replacement of the thienyl ring from LASSBio-294 (4) and LASSBio-785 (5) for the phenyl, furanyl and pyrrolyl rings, aiming at determining the structure-associated events of the methyl group to the vasodilator profile of these NAH compounds.

Section snippets

Results and discussion

The synthesis of the new N-acylhydrazone derivatives (6a–c) was carried out as outlined in Scheme 1. The starting material was 3,4-methylenedioxybenzoylhydrazine (8) that can be obtained from natural safrole (3) in 57% overall yield as described previously [7]. The acid-catalyzed condensation of the hydrazide (8) with the corresponding aromatic or heteroaromatic aldehydes resulted in LASSBio-294 (4) and its desired isosteric N-acylhydrazone derivatives LASSBio-129 (6a), LASSBio-123 (6b) and

Conclusions

In this report, we have showed for the first time that the methyl group, bridged to the amide bond of NAH, plays an important role in the vasodilatory activity of these compounds by inducing conformational changes supported by crystallography, molecular modeling and UV studies. The structural modifications introduced by the methyl group are certainly required to the vasodilator effectiveness and potency increase observed for the N-methyl-NAH series, as well as to promote changes in its

General information

Melting points were determined with a Quimis 340 apparatus and are uncorrected. ¹H NMR spectra were determined in deuterated chloroform or dimethyl sulfoxide containing ca. 1% tetramethylsilane as an internal standard, using a Bruker DPX-200 at 200 MHz. ¹³C NMR spectra were determined in the same spectrometer at 50 MHz, employing the same solvents. Microanalyses were carried out using a Perkin Elmer 240 analyzer and Perkin Elmer AD-4 balance. The progress of all reactions was monitored by thin

Acknowledgments

Special thanks are due to CAPES (BR.), CNPq (BR.), PRONEX (BR.) and FAPERJ (BR.) for financial support and fellowships.

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Original articleStudies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General information

Acknowledgments

Am. J. Hypertens.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Tetrahedron Lett.

JAMA

J. Clin. Hypertens. (Greenwich)

Quim. Nova

Original article
Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives