Antifungal Evaluation of Bis Mannich Bases Derived from Acetophenones and Their Corresponding Piperidinols and Stability Studies

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(b b-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 C1 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 m mg/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.

Screening of antimicrobial activity of essential oil and methanol extract of Satureja hortensis on foodborne bacteria and fungi

“…MIC values of the fungi isolates were studied based on the agar dilution method as described previously by Gul et al (2002). The essential oils of Satureja hortensis were added aseptically to sterile molten PDA medium, containing Tween 20 (Sigma 0.5%, v/v), in the volume appropriate to produce the concentration range of 7.8-500 µg/ml.…”

Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

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Mannich bases have several biological activities such as antimicrobial, [1][2][3][4][5] cytotoxic, [6][7][8][9] anticancer, 10) analgesic, 11) anti-inflammatory, 12,13) diuretic 14,15) and anticonvulsant [16][17][18][19] activities. An amino ketone, Mannich base, containing at least one activated hydrogen atom at the b position to an amino function, can undergo deamination in vivo 20) or under simulated in vitro conditions 1,3,6) to liberate the corressponding a,b-unsaturated ketones.

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“…The a,b-unsaturated ketone is an active center for nucleophilic attack. The biological activities of Mannich bases, such as antimicrobial, [1][2][3]21,22) cytotoxic and anticancer 6,9,23) activities, have been attributed to these liberated a,b-unsaturated ketones which can alkylate nucleophiles, especially thiol groups 1,6,24,25) rather than amino and hydroxyl groups, 26) by Michael type addition reactions of nucleophiles to a,b-unsaturated ketones.27) In addition, enzyme-catalyzed alkylation of the thiol group of cystein with a,b-unsaturated carbonyl compounds has been observed. …”

“…An amino ketone, Mannich base, containing at least one activated hydrogen atom at the b position to an amino function, can undergo deamination in vivo 20) or under simulated in vitro conditions 1,3,6) to liberate the corressponding a,b-unsaturated ketones. The a,b-unsaturated ketone is an active center for nucleophilic attack.…”

“…Production of thiol adducts in the stability studies, 1,3,6) carried out under in vitro physiological conditions (in phosphate buffer with pH 7.4, at 37°C), with 2-mercaptoethanol, various unsaturated ketones or Mannich bases, suggests that a,bunsaturated ketones and Mannich bases producing unsaturated ketones by deamination to exert their antimicrobial activities by thiol alkylation of unsaturated ketones.…”