Evaluation of Cytotoxicity of Some Mannich Bases of Various Aryl and Arylidene Ketones and Their Corresponding Arylhydrazones

Dimmock, Jonathan R.; Advikolanu, K.M.; Scott, Halee; Duffy, Michael J.; Reid, R. S.; Quail, J. Wilson; Jia, Z.; Hickie, Robert A.; Allen, T. W.; Rutledge, John; Tempest, M. L.; Oreski, A. B.

doi:10.1002/jps.2600811203

Cited by 19 publications

(6 citation statements)

References 3 publications

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“…Deamination process is important to evoke biological responses. An amino ketone possessing at least one activated hydrogen atom at the β position to an amino group can undergo deamination in vivo or under simulated in vitro conditions to generate the corresponding α,β-unsaturated ketone [10,11]. The biological activities of Mannich bases have been attributed to these liberated α,βunsaturated ketones by alkylating nucleophils, especially thiol groups [1,12].…”

Section: Introductionmentioning

confidence: 99%

Antifungal Activity of Some Mono, Bis and Quaternary Mannich Bases Derived from Acetophenone

Gül

Ojanen

Vepsäläinen

et al. 2011

Arzneimittelforschung

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The development of resistance to current antifungal therapeutics drives search for new effective agents. Some Mannich bases have antifungal activity, but no information is available regarding the antifungal activity of acetophenone derived Mannich bases. Mono Mannich bases of acetophenone 1-3 were synthesized and converted into their corresponding bis derivatives, 5-7. Representative quaternary derivatives 4 and 8 were also synthesized. Antifungal activities of the compounds were evaluated using some yeasts and dermatophytes in vitro. Mono Mannich base 3 and quaternary compounds 4 and 8 were found to be 2-16 times more potent than the reference compound amphotericin B against dermatophytes: Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum canis. Compounds 4 and 8 were also found to be 2 times more effective compared with amphotericin B against the yeast Saccharomyces cerevisiae. Quaternization procedure improved the biological activity dramatically, whereas conversion of mono Mannich bases to corresponding bis derivatives generally did not affect antifungal activity. Our results suggest that acetophenone derived mono Mannich base 3 and quaternary derivatives 4 and 8 may serve as leading compounds for further studies to develop new antifungal agents with their highly potent antifungal activity.

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Section: Introductionmentioning

confidence: 99%

Antifungal Activity of Some Mono, Bis and Quaternary Mannich Bases Derived from Acetophenone

Gül

Ojanen

Vepsäläinen

et al. 2011

Arzneimittelforschung

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“…MKs can also be used as prodrugs [4], [5]. Furthermore, unsaturated MKs are efficient alkylating agents for thiol enzymes [6], [7] and their water solubility, especially in the case of the aminoketones, makes them good model compounds for antimicrobial investigations.…”

Section: Introductionmentioning

confidence: 99%

Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans

et al. 2013

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We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C. albicans and the closely related C. parapsilosis and C. krusei while having reduced efficacy toward C. glabrata and almost no efficacy against Aspergillus sp. Transcript profiling of C. albicans cells exposed for 30 or 60 min to 2-(morpholinomethyl)-1-indanone, a representative FMK with a five-membered saturated ring, revealed a transcriptional response typical of oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator. Consistently, C. albicans lacking the CAP1 gene was hypersensitive to this FMK, while C. albicans strains overexpressing CAP1 had decreased sensitivity to 2-(morpholinomethyl)-1-indanone. Quantitative structure–activity relationship studies revealed a correlation of antifungal potency and the energy of the lowest unoccupied molecular orbital of FMKs and unsaturated Mannich ketones thereby implicating redox cycling-mediated oxidative stress as a mechanism of action. This conclusion was further supported by the loss of antifungal activity upon conversion of representative FMKs to aminoalcohols that were unable to participate in redox cycles.

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“…[333435] These α-, β-unsaturated ketones are very sensitive for Michael addition to alkylate certain cellular constituents especially thiol groups. [3336] Among these cellular thiols, glutathione (GSH) is the most abundant, and Mannich bases are reported to inhibit one or more of the following enzymes in the GSH metabolism namely GSH S-transferases, GSH reductase, gamma-glutamyl transpeptidase, and GSH peroxidase.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, hematological, biochemical, and neurotoxicity screening of some Mannich base hydrochlorides

et al. 2013

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Background:Mannich bases are an important class of compounds in medicinal chemistry with a wide spectrum of biological activities, however, knowledge on their toxicity is limited.Materials and Methods:Two Mannich base hydrochlorides 1a (2-thienyl-β-dimethylaminoethyl ketone hydrochloride) and 1b (β-dimethylaminopropiophenone hydrochloride) were synthesized and characterized on the basis of their infrared and nuclear magnetic resonance spectral data. The potential effects of the synthesized compounds (5 mg/kg, i.p, during 30 days) on relative weight, hematological parameters, biochemical parameters, and neurotoxicity were tested using male Wistar rat.Results:The results showed that compound 1b alters body weight on the first 10 days (182%, P < 0.01) and on the last 10 days (107%, P < 0.01) of treatment. The same treatment decreases food intake (P < 0.01) and increases water intake (P < 0.05). Both compounds induced a deficit on rotarod test manifested by a decrease of grasping time (1a: 65.33%, P < 0.01; 1b: 60.55%, P < 0.01) and fall time (1a: 59.75%, P < 0.01; 1b: 56.81%, P < 0.01) only on the last day of training. Moreover, Mannich base 1b decreases the liver relative weight (22.24%, P < 0.01). It was also observed that both products decrease the total serum cholesterol (Ch) levels (1a: 52.87%, P < 0.01; 1b: 64.70%, P < 0.01). Interestingly, compounds 1a and 1b affect hematological parameters manifested by an increase of the number of white blood cells (1a: 32.29%, P < 0.05; 1b: 20.64%, P < 0.05) and red blood cells (RBCs) (1a: 12.57%, P < 0.05; 1b: 20.11%, P < 0.05), an increase of red cell hemoglobin concentration (1a: 10.48%, P < 0.05; 1b: 16.12%, P < 0.05) and of the volume occupied by RBCs or hematocrit (1a: 18.28%, P < 0.05; 1b: 15.56%, P < 0.05), and an increase of the number of platelets (1a: 16.80%, P < 0.05; 1b: 39.96%, P < 0.05) accompanied by a decrease in hemoglobin level only with the compound 1a (7.41%, P < 0.05).Conclusion:These results show that both compounds 1a and 1b induced a hypoxia status associated to low level of Ch and liver toxicity. The deficit observed by rotarod could be explained by the myorelaxant effect of the used products.

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Evaluation of Cytotoxicity of Some Mannich Bases of Various Aryl and Arylidene Ketones and Their Corresponding Arylhydrazones

Cited by 19 publications

References 3 publications

Antifungal Activity of Some Mono, Bis and Quaternary Mannich Bases Derived from Acetophenone

Antifungal Activity of Some Mono, Bis and Quaternary Mannich Bases Derived from Acetophenone

Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans

Synthesis, hematological, biochemical, and neurotoxicity screening of some Mannich base hydrochlorides

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