Synthesis, Hematological, Biochemical, and Neurotoxicity Screening of Some Mannich Base Hydrochlorides

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Biochemical, hematological, hypoxia, Mannich bases, myorelaxant, neurotoxicity


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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Lahbib, K., Aouani, I., Abdelmelek, H., & Touil, S. (2018). Synthesis, Hematological, Biochemical, and Neurotoxicity Screening of Some Mannich Base Hydrochlorides. Toxicology International, 20(3), 268–274. Retrieved from



Original Research
Received 2018-08-10
Accepted 2018-08-10
Published 2018-08-10



Mannich C, Krösche W. About a condensation product of formaldehyde, ammonia and antipyrine. Archiv of pharmacy Med Chem 1912;250:647"‘67.

Blicke FF. The Mannich reaction. John Wiley and Sons Organic reaction 1942;1:303"‘41.

Mete E, Ozelgul C, Kazaz C, Yurdakul D, Sahin F, Gul H. Synthesis and antifungal activity of 1"‘aryl"‘3"‘phenethylamino"‘1"‘propanone hydrochlorides and 3"‘aroyl"‘4"‘aryl"‘1"‘phenethyl"‘ 4"‘piperidinols.

Arch Pharm 2010;343:291"‘300.

Gul HI, Sahin F, Gul M, Ozturk S, Yerdelen KO. Evaluation of antimicrobial activities of several mannich bases and their derivatives. Arch Pharm (Weinheim) 2005;338:335"‘8.

Gul HI, Denizci AA, Erciyas E. Antimicrobial evaluation of some mannich bases of acetophenone and representative quaternary derivatives. Arzneimittelforschung 2002;52:773"‘7.

Gul HI, Ojanen T, Vepsalainen J, Gul M, Erciyas, E, Hanninen O.Antifungal activity of some mono, bis and quaternary mannich bases derived from acetophenone. Arzneimittelforschung 2001;51:72"‘5.

Reddy MV, Su CR, Chiou WF, Liu YN, Chen RY, Bastow KF, et al.Design, synthesis, and biological evaluation of Mannich bases of heterocyclicchalcone analogs as ctytotoxic agents. Bioorg Med Chem 2008;16:7358"‘70.

Gul M. Cytotoxic and antifungal acetophenone"‘derived Mannich bases: Effects on redox thiols and heat shock proteins. PhD Thesis, Kuopio University, Kuopio, Finland, 2005.

Dimmock JR, Vashishtha SC, Quail JW, Pugazhenthi U, Zimpel Z, Sudom AM, et al . 4 "‘ B "‘Arylvinyl . "‘ 3 "‘ B"‘arylvinylketo."‘1"‘ethyl"‘4"‘piperidinols and related compounds: A novel class of cytotoxic and anticancer agents. Med Chem 1998;41:4012"‘20.

Dimmock JR, Kumar P. Anticancer and cytotoxic properties of Mannich bases. Curr Med Chem 1997;4:1"‘22.

Gul HI, Suleyman H, Gul M. Evaluation of the anti"‘inflammatory activity of N, N'"‘Bis (3"‘dimethylamino"‘1"‘phenyl"‘propylidene) hydrazine dihydrochloride. Pharm Biol 2009;47:968"‘72.

Suleyman H, Gul HI, Gul M, Alkan M, Gocer F. Anti"‘inflammatory activity of bis (3"‘aryl"‘3"‘oxo"‘propyl) methylamine hydrochloride in rat. Biol Pharm Bull 2007;30:63"‘7.

Sridhar SK, Ramesh A. Synthesis and pharmacological activities of hydrazones, Schiff and Mannich bases of isatin derivatives.Biol Pharm Bull 2001;24:1149"‘52.

Suleyman H, Gul HI, Asoglu M. Anti"‘inflammatory activity of 3"‘benzoyl"‘1"‘methyl"‘4"‘phenyl"‘4"‘piperidinol hydrochloride.Pharmacol Res 2003;47:471"‘5.

Malinka W, Swiatek P, Filipek B, Sapa J, Jezierska A, Koll A.Synthesis, analgesic activity and computational study of new isothiazolopyridines of Mannich base type. Farmaco 2005;60:961"‘8.

Selvakumar V, Duraipandi S, Devdas S. Synthesis and Psychopharmacological activities of some Succinimide Mannich bases. J Pharm Res 2011;4:3168"‘3170.

Gul HI, Calls U, Ozturk Z, Tutar E, Calikiran L. Evaluation of anticonvulsant activities of bis (3"‘aryl"‘3"‘oxo"‘propyl) ethylamine hydrochlorides and 4"‘aryl"‘3"‘arylcarbonyl"‘1"‘ethyl"‘4"‘piperidinol hydrochlorides. Arzneimittelforschung 2007;57:133"‘6.

Gul HI, Calis U, Vepsalainen J. Synthesis of some mono"‘Mannich bases and corresponding azine derivatives and evaluation of their anticonvulsant activity. Arzneimittelforschung 2004;54:359"‘64.

Sriram D, Yogeeswari P, Gopal G. Synthesis, anti"‘HIV and antitubercular activities of lamivudine prodrugs. Eur J Med Chem 2005;40:1373"‘6.

Sriram D, Bal TR, Yogeeswari P. Design, synthesis and biological evaluation of novel non"‘nucleoside HIV"‘1 reverse transcriptase inhibitors with broad"‘spectrum chemotherapeutic properties.Bioorg Med Chem 2004;12:5865"‘73.

Sriram D, Yogeeswari P. Towards the design and development of agents with broad spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS. Curr Med Chem 2003;10:1689"‘95.

Pandeya SN, Sriram D, Nath G, DeClercq E. Synthesis, antibacterial, antifungal and anti"‘HIV activities of Schiff and Mannich bases derived from isatin derivatives and N"‘[4"‘(4"²"‘chlorophenyl) thiazol"‘2"‘yl] thiosemicarbazide. Eur J Pharm Sci 1999;9:25"‘31.

Pandeya SN, Sriram D, Nath G, De Clercq E. Synthesis, antibacterial, antifungal and anti"‘HIV activity of Schiff and Mannich bases of isatin with N"‘[6"‘chlorobenzthiazole"‘2"‘yl] thiosemicarbazide. Indian J Pharm Sci 1999;61:358"‘61.

Pandeya SN, Sriram D, Nath G, De Clercq E. Synthesis, antibacterial, antifungal and anti"‘HIV evaluation of Schiff and Mannich bases of isatin derivatives with 3"‘amino"‘2"‘methylmercapto quinazolin"‘4 (3H)"‘one. Pharm Acta Helv 1999;74:11"‘7.

Friebolin W, Jannack B, Wenzel N, Furrer J, Oeser T, Sanchez CP, et al. Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum. Med Chem 2008;51:1260"‘77.

Miroshnikova OV, Hudson TH, Gerena L, Kyle DE, Lin AJ. N,N'"‘(1,4"‘Phenylene) bis (2"‘bromo"‘2"‘methylpropanamide). J Med Chem 2007;50:889"‘96.

Lee B, Bauer H, Melchers J, Ruppert T, Rattray L, Yardley V, et al. Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: A divinyl ketone as key intermediate. J Med Chem 2005;48:7400"‘10.

Davioud"‘Charvet E, McLeish MJ, Veine DM, Giegel D, Arscott LD, Andricopulo AD, et al. Mechanism"‘based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity. Biochemistry 2003;42:13319"‘30.

Kidwai M, Thakur R, Mohan R. Ecofriendly synthesis of novel antifungal (thio) barbituric acid derivatives. Acta Chim Slov 2005;52:88"‘92.

Kocsis B, Kustos I, Kilár F, Nyul A, Jakus PB, Kerekes S, et al.Antifungal unsaturated cyclic Mannich ketones and amino alcohols: Study of mechanism of action. Eur J Med Chem 2009;44:1823"‘9.

Mazzei M, Nieddu E, Miele M, Balbi A, Ferrone M, Fermeglia M, et al. Activity of Mannich bases of 7"‘hydroxycoumarin against Flaviviridae. Bioorg Med Chem 2008;16:2591"‘605.

Kumaria N, Dwivedi AK, Maikhuri JP, Gupta G, Habib S, Dhar JD, et al. Substituted acrylophenones and related mannich bases as possible spermicides and inhibitors of HIV envelope glycoprotein"‘CD4 interaction. Eur J Med Chem 2002;37:855"‘64.

Erciyas E, Erkaleli HI, Cosar G. Antimicrobial evaluation of some styryl ketone derivatives and related thiol adducts. J Pharm Sci 1994;83:545"‘8.

Dimmock JR, Advikolanu KM, Scott HE, Duffy MJ, Reid RS, Quail JW, et al. Evaluation of cytotoxicity of some Mannich bases of various aryl and arylidene ketones and their corresponding arylhydrazones. J Pharm Sci 1992;81:1147"‘52.

Gordon PN, Johnston JD, English AR. Antimicrobial Agents and Chemotherapy. Hobby GL, Editor. American Society for Microbiology; Bethesda; 1965. p. 165.

Dimmock JR, Kumar P, Chen M, Quail JW, Yang J, Allen TM, et al. Synthesis and cytotoxic evaluation of mesna adducts of some 1"‘aryl"‘4,4"‘dimethyl"‘5"‘(1"‘piperidino)"‘1"‘penten"‘3"‘one hydrochlorides. Pharmazie 1995;50:449"‘53.

Dimmock JR, Kumar P, Manavathu EK, Obedeanu N, Grewal J.Activity of some Mannich bases of conjugated styryl ketones against Candida albicans. Pharmazie 1994;49:909"‘12.

Cairns J. Efficiency of the adaptive response of Escherichia coli to alkylating agents. Nature 1980;286:176"‘8.

Farmer PB. Monitoring for human exposure to carcinogens.Chem Br 1982;18:790"‘4.

Muthumani P, Neckmohammed R, Meera S, Venkataraman N, Chidambaranathan P, Devi CA, et al. Synthesis and evaluation of anticonvulsant and antimicrobial activities of some Mannich bases of substituted aminophenol and acetophenone. Int J Pharm Biomed Res 2010;1:78"‘86.

Maxwell CE. β"‘dimethylaminopropiophenone hydrochloride.Organic Syntheses 1955;3:305.

NRC [National Research Council]. Guide for the care and use of laboratory animals. National institutes of Health, Bethesda 1985:23-85.

Auvray N, Caston J, Reber A, Stelz T. Role of the cerebellum in the ontogenesis of the equilibrium behavior in the young rat: A behavioral study. Brain Res 1989;505:291"‘301.

Caston J, Delhaye"‘Bouchaud N, Mariani J. Motor behavior of heterozygous staggerer mutant (+/sg) versus normal (+/+) mice during aging. Behav Brain Res 1995;72:97"‘102.

Jeljeli M, Strazielle C, Caston J, Lalonde R. Effects of ventrolateral"‘ventromedial thalamic lesions on motor coordination and spatial orientation in rats. Neurosci Res 2003;47:309"‘16.

Zion C, Auvray N, Caston J, Reber A, Stelz T. Effects of cerebellectomy at day 15 on the ontogenesis of the equilibrium behavior in the rat. Brain Res 1990;515:104"‘10.

Fossati P, Melzi d'Eril GV, Tarenghi G, Prencipe L, Berti G. A kinetic colorimetric assay of gamma"‘glutamyltransferase. Clin Chem 1986;32:1581"‘4.

Trinder P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 1969;6:24"‘7.

Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem 1989;264:13963"‘6.

Cunningham ML, Price HC, O'Connor RW, Moorman MP, Mahler JF, Nold JB, et al. Inhalation toxicity studies of the alpha, beta"‘unsaturated ketones: 2"‘cyclohexene"‘1"‘one. Inhal Toxicol 2001;13:25"‘36.

Gul HI, Vepsalainen J, Gul M, Erciyas E, Hanninen O. Cytotoxic activities of mono and bis Mannich bases derived from acetophenone against Renca and Jurkat cells. Pharm Acta Helv 2000;74:393"‘8.

Rodrigues AL, Rosa JM, Gadotti VM, Goulart EC, Santos MM, Silva AV, et al. Antidepressant"‘like and antinociceptive"‘like actions of 4"‘ (4'"‘chlorophenyl)"‘6"‘ (4''"‘methylphenyl)"‘2"‘ hydrazinepyrimidine Mannich base in mice. Pharmacol Biochem Behav 2005;82:156"‘62.

Dunhan N, Miya T. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc Am Pharm Assoc 1957;46:208"‘9.

Shiozawa A, Narita K, Izumi G, Kurashige S, Sakitama K, Ishikawa M.Synthesis and activity of 2"‘methyl"‘3"‘aminopropiophenones as centrally acting muscle relaxants. Eur J Med Chem 1995;30:85"‘94.

Hasegawa A, Furuhama K. Atlas of the hematology of the laboratory rat. University of Michigan: Elsevier; 1998. p. 152.

Morgan DL, Price HC, O'Connor RW, Seely JC, Ward SM, Wilson RE, et al. Upper respiratory tract toxicity of inhaled methylvinyl ketone in F344 rats and B6C3F1 mice. Toxicol Sci 2000;58:182"‘94.

Morgan DL, Ward SM, Wilson RE, Price HC, O'Connor RW, Seely JC, et al. Inhalation toxicity studies of the alpha, beta"‘unsaturated ketones: Ethyl vinyl ketone. Inhal Toxicol 2001;13:633"‘58.

Ji L, Long Q, Yang D, Xie J. Identification of mannich base as a novel inhibitor of Mycobacterium tuberculosis isocitrate by high"‘throughput screening. Int J Biol Sci 2011;7:376"‘82.