A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives

Abstract

In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC(50) = 0.04 microM), which is 20 times more active than diltiazem (EC(50) = 0.79 microM), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.

Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones

“…We identified oxadiazolothiazin-3-ones [4], a class of compounds that, if properly decorated, block LTCC [1,2] or reverse the multi-drug resistance (MDR) activity [5]. LTCC belong to the well-established panel of proteins targeted to treat cardiovascular diseases (the primary cause of death in the western world), whereas MDR is the cell resistance to structurally and functionally distinct drugs, a property targeted to treat cancer (the second cause of death in the western world).…”

Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

“…All these properties, in particular their low activity on cardiac functionality, may have potential therapeutic relevance prompting us for future modifications of chemical structures in order to obtain more active substances and in vivo studies. [25] b From reference [23] c Activity: decrease in developed tension in isolated guinea-pig left atrium at 10 6 M, expressed as percent changes from the control (n=4-6). The left atria were driven at 1 Hz.…”

“…In this context some time ago we started a series of experiments to study the ability of different diltiazem-like compounds, some of which have already demonstrated good cardiodepressant activities [22,23], to compete for excretion with the typical target of Pgp-170 activity, doxorubicin, causing its accumulation into multidrugresistant A2780/DX3 cells [24].…”

“…The potentiation of doxorubicin-driven apoptosis was also tested with the diltiazem-like compound 3 [23] (Fig. 1) that in our previous work [24] demonstrated a high potency in terms of inhibition of the MDR1 activity.…”

Solvent-free microwave-promoted Michael addition of aza-nucleophiles to benzo[b]thiophen-2-yl-2-propenone

“…8,9 The addition of thiols to α,β-unsaturated carbonyl compounds results in the synthesis of biologically active compounds, such as the calcium antagonist diltiazem. 10,11 Gomtsyan et-al 12,13 reported the synthesis of β-aminoketones from N-methoxy amides (Weinreb amides) through a novel sequential transformation consisting of nucleophilic substitution with vinyl-Grignard reagents, followed by a Michael-type reaction with a number of amines. The reaction proceeds in good yields for a variety of amides, vinyl Grignard reagents, and N-nucleophiles.…”