[(Aminomethyl)aryloxy]acetic acid esters. A new class of high-ceiling diuretics. 1. Effects of nitrogen and aromatic nuclear substitution.

Journal of Medicinal Chemistry (Impact Factor: 5.45). 01/1985; 27(12):1579-87.
Source: PubMed


A series of Mannich bases and aminomethyl derivatives of ethyl [2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetate were synthesized and tested for saluretic and diuretic activities. The effects of nitrogen and aromatic nuclear substitution, reorientation of the aminomethyl group relative to that of the phenolic hydroxyl group, and replacement of either the phenolic hydroxyl or the aminomethyl group by other functional groups are described. Ethyl [2,3-dichloro-4-[3-(aminomethyl)-4-hydroxybenzoyl]phenoxy]acetate (27) was found to be a very potent, high-ceiling diuretic.

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    • "Various biological activities of Mannich bases, including cytotoxic (Dimmock and Kumar, 1997; Gul et al., 2000a, 2002c,d,f, 2003a,b), anti-cancer (Siatra-Papastaikoudi et al., 1994), analgesic (Pilli et al., 1992), anti-inflammatory (Suleyman et al., 2003), diuretic (Lee et al., 1984), anti-microbial (Erciyas et al., 1994; Gul et al., 2002b,e, 2001a) and anti-convulsant (Dimmock et al., 1992b; Gul et al., 2002a, 2004) activities, have been reported. Cytotoxicity of Mannich bases has been attributed to the liberated a,b-unsaturated ketones following deamination under in vivo and simulated in vitro conditions (Dimmock et al., 1992a; Erciyas et al., 1994; Gul et al., 2002c,e). "
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    ABSTRACT: Mannich bases interact with cellular thiols and inactivate thioredoxin reductase. In this study, the effects of cytotoxic mono-Mannich bases 2, 3 and cyclic Mannich base C1 on the expression of cytoprotective heat shock proteins (HSC70 and GRP75) and on levels of thioredoxin (TRX) and glutaredoxin (GRX) were investigated in Jurkat cells. Cells were exposed to the compounds for 24 h in cell culture medium with 1% FBS. C1 and 2 increased the levels of HSC70 (200% of control) in all the concentrations tested, but 3 did not affect HSC70 levels. Whereas 3 increased GRP75 expression (123-154%), 2 and C1 either did not affect (95-87% for 2, and 88% for C1) or slightly decreased GRP75 expression (82% for 2 and 67% for C1). Mannich bases generally decreased GRX levels (68%, 63-77% and 33-71% for 2, 3 and C1, respectively), but 3 increased GRX levels at 1 microg/ml (142%). Whereas 2 and 3 decreased TRX levels (30-79% and 37-44% of control, respectively), C1 increased the expression of TRX (156-201%). Our results suggest that decreases in GRX and TRX due to the alkylating effects of Mannich bases might have prevented cell division and decreased survival in Jurkat cells, which could not be prevented by increased heat shock protein expression.
    Full-text · Article · Sep 2005 · Toxicology in Vitro
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    ABSTRACT: 3-Amino-5-sulfamoylbenzoic acids and several series of (aryloxy)alkanoic acids were evaluated for their inhibitory effects on two human erythrocyte ion transport systems — the Na+, K+ cotransport system and the DIDS-sensitive anion carrier. Several classic loop diuretics, including the (aryloxy)alkanoic acid-ethacrynic acid and several 3-amino-5-sulfamoylbenzoic acids, like bumetanide and furosemide, displayed relatively strong inhibitory activity versus the cotransport system with relatively weaker action versus the anion carrier. Furthermore, diuretic potency correlated with cotransport inhibitory potency. Another class of (aryloxy)alkanoic acids, namely the [(2,3-dihydro-1 H-inden-5-yl)oxy]acetic acids, such as indacrinone and MK-473, which exhibit less potent loop dacrinone and MK-473, which exhibit less potent loop diuretic activity, were less potent cotransport inhibitors and more effective inhibitors of the anion carrier. Still other (aryloxy)alkanoic acids, with little saliuretic activity, namely a sub-class of [(2,3-dihydro-1 H-inden-5-yl)oxy]alkanoic acids and a series of [(2,3,9,9a-tetrahydro-1 H-fluoren-7-yl)oxy]acetic acids displayed little or no inhibitory action on the cotransport system but enhanced inhibitory action on the anion carrier. Most interestingly, the relative anion carrier inhibitory potency correlated well with the relative inhibitory activity of each compound on bicarbonate-stimulated cell swelling in cat cerebrocortical slices.
    No preview · Article · Nov 1986 · Archiv für Experimentelle Pathologie und Pharmakologie
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    ABSTRACT: The development of resistance to current antifungal therapeutics drives the search for effective new agents. The fact that some acetophenone-derived Mannich bases had shown antifungal activities in our previous studies led us to design and synthesize acetophenone-derived bis Mannich bases, B1-B5, bis(beta-aroylethyl)methylamine hydrochlorides, to evaluate their antifungal activity. These bis Mannich bases were then converted to the corresponding piperidinols, C1-C5, which are structural isomers of bis derivatives, 3-aroyl-4-aryl-1-methyl-4-piperidinol hydrochlorides, to see alterations in biological activity. A stability study of B1 and Cl was also carried out to estimate whether they alkylate the thiols. All compounds studied have shown antifungal activity, especially against dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, and Microsporum canis), in the concentration range studied (2-128 microng/ml). The activity was especially apparent against T. tonsurans. All compounds had at least equal antifungal activity compared with the reference compound amphotericin-B against T. tonsurans. Bis Mannich bases were generally found to be more potent compounds than their structural isomer piperidinols. The results of our stability studies suggest that thiol alkylation may contribute to the antifungal activity of the Mannich bases synthesized. Even though all compounds showed antifungal activity against dermatophytes, bis Mannich bases B1, B2, B4, and B5 appear to have potential for developing novel antifungal agents against dermatophytes.
    Preview · Article · Nov 2002 · Biological & Pharmaceutical Bulletin
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