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Hydrolysis of N-Mannich bases and its consequences for the biological testing of such agents

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Abstract

Although N-Mannich bases of amides, imides, hydantoins and various other NH-acidic compounds have been known for a long time, and several drug substances and other compounds bearing an NH-acidic group have been modified by N-aminomethylation and tested as potential medicinal agents, the facile decomposition of several N-Mannich bases in aqueous solution has not been generally recognized. In this paper recent kinetic studies by the authors on the stability of a great number of N-Mannich bases are summarized and used to show that several previous reports on biological testing of various N-Mannich bases may be unrealistic because of very rapid decomposition of the derivatives in aqueous medium. The structural factors influencing the decomposition rate of N-Mannich bases are discussed and structure-reactivity relationships are given which may be useful for the prediction of stability of new N-Mannich bases as well as for retrospective evaluations.

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... The literature mentions that Mannich bases still arouse interest to be studied due to the fact that they are potential medicinal agents [42]. The hydrogen atom of the imino group in the pyrazole ring is acidic enough to participate in the Mannich reaction. ...
... The literature mentions that Mannich bases still arouse interest to be studied the fact that they are potential medicinal agents [42]. The hydrogen atom of th group in the pyrazole ring is acidic enough to participate in the Mannich reaction fore, Mannich bases can be obtained by multicomponent condensation between erocyclic nucleus with the acid nitrogen atom (NH); 2. Formaldehyde; and 3. a sec amine [43]. ...
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... The ideal way to observe the appearance of drug from prodrug is by actual studies in humans. But as the prodrugs are new drugs, it is not feasible to perform in vivo studies directly on humans [3][4][5][6][7] . Rabbit was selected as an animal model to study the release pattern of prodrug as there are some physiological similarities of rabbits with humans. ...
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... It was established that the acidity of the parent amide and steric effects within the amine component correlate with reactivity [85,89]. For amines with similar steric properties, a decreasing basicity is associated with decreasing reactivity [85] . ...
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The kinetics of decomposition of various N-Mannich bases of salicylamide in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for amino compounds. The decomposition, yielding salicylamide, amine and formaldehyde in stoichiometric amounts, showed bell-shaped pH-rate profiles which could be accounted for by assuming spontaneous decomposition of both neutral and protonated Mannich base and unreactivity of the derivatives in the anionic form. For the Mannich bases with the amines piperidine, α-alanine, methylamine and morpholine, the half-lives of decomposition at pH 7.40 and 37°C were 14, 17, 28 and 41 min, respectively, suggesting that salicylamide N-Mannich bases are possible candidates as pro-drugs for compounds containing a primary or secondary amino group. N-Amidomethylation of the amines with salicylamide resulted in a pronounced lowering of their basicity corresponding to 3–4 pKa units which may be of potential utility for the application of N-Mannich bases as pro-drug forms for amines.
Article
The υ steric parameters for alkyl, alkoxy, thioalkyl, dialkylamino, and oxyalkyl groups and the υ′ values of alkyl groups were correlated with equations derived from the relationship υ = anα + bnβ + cnγ + dnδ + i, with excellent results. The parameters nα, nβ, nγ, and nδ represent the number of α, β, γ, and δ carbon atoms, respectively. The correlation equations make possible the estimation of υ values for a very large number of groups. The ESc values of Hancock and the ESo values of Palm are simply steric parameters with different values of α from that obtained for the υ values. Rate constants for nucleophilic substitution of benzyl chloride by alkoxide ions, of allyl bromide and of 1-chloro-2,4-dinitrobenzene by alkylamines, of alkaline hydrolysis of ethyl 4-nitrophenyl alkyl phosphonates, C-substituted amides, O-substituted esters, and dialkylphenylacetonitriles, of acidic hydrolysis of C-substituted amides, and of the reaction of alcohols with 4-nitrobenzoyl chloride have been successfully correlated with the equation QAk = anα + bnβ + cnγ + i. Evaluation of the effect on branching shows clearly that for alkyl groups which are not symmetric, no one set of steric parameters will be effective in all types of reactions.
Article
The antimicrobial and antifungal activities of 29 congeneric isatin N-Mannich bases were investigated by testing against standard test microorganisms and 21 pathogenic Gram-negative microorganisms. Considerable growth inhibition of Gram-negative bacteria and yeasts and slight inhibition of Gram-positive bacteria resulted when they were treated with the various N-Mannich bases of isatin and 5-nitroisatin, respectively.
Article
The preparation of a series of 3-substituted 2-benzoxazolinones is described. These compounds were screened for their antibacterial properties; most compounds have shown significant antibacterial activity.
Article
The synthesis and the structure of some aminomethyl derivatives of 1-cyclohexylbarbituric acids, obtained by the Mannich reaction, are described. Acids, containing a pyrrolidinomethyl group in the position 5 were found to have the barbituric ring in the enolic form, stabilized by a hydrogen bond with the pyrrolidine nitrogen atom. Some of the described compounds displayed antiinflammatory activity.
Article
The antimicrobial and antifungal activities of 29 congeneric isatin N-Mannich bases were investigated by testing against standard test microorganisms and 21 pathogenic Gram-negative microorganisms. Considerable growth inhibition of Gram-negative bacteria and yeasts and slight inhibition of Gram-positive bacteria resulted when they were treated with the various N-Mannich bases of isatin and 5-nitroisatin, respectively.
Article
Nach dem unten aufgeführten Reaktionsschema werden aus dem Dicarbonsäuren (II) die Succinsäurederivate (I), (III), (IV), (VI), (VII) und (VIII) dargestellt.
Article
1'-Substituted spiro[fluorene-9,3'-pyrrolidine-2',5'-diones], 1',1''' - (1,4-piperazinediyldimethylene) bis[spiro[fluorene-9,3'-pyrrolidine-2',5'-dione]], and 1'-arylspiro[fluorene-9,3'-pyrrolidines] were synthesized from spiro[fluorene-9,3'-tetrahydrofuran-2',5'-dione]. The rat passive cutaneous anaphylaxis assay showed that one compound possessed slight antiallergic activity. Synthesis of 3-substituted 1-aryl-4-oxospiro[azetidine-2,9'-fluorenes] and 1,1''-p-phenylenebis[4-oxospiro[azetidine-2,9'-fluorenes]] was achieved via the reaction of appropriate N-fluorenylideneanilines with tert-butylcyanoketene and cyclopentamethyleneketene, respectively.
Article
The synthesis and pharmacological screening of a series of new phenylsuccinimide derivatives are described. Seven compounds of that series elicited a marked anticonvulsant activity. Among the compounds tested, interesting structures were those metasubstituted with bromine, fluorine or trifluoromethyl group. The most interesting drug seems to be the N-morpholinemethyl derivative of mbromophenylsuccinimide, which has a long duration of activity, elicits a very strong antipentetrazole action, and gives good protection against maximal electroshock seizures.
Article
Preliminary antiviral, antibacterial, and antifungal screening results of a series of isatin N-Mannich bases are provided.
Article
A number of N-heteroparaffinomethyl-1H-benzazoles is obtained by the Mannich and allied syntheses. Amine salts of all but the indoles are prepared. The degree of motricity and toxic levels are ascertained for the title compounds. Three major molecular modifications investigated cause variations in pharmacodynamic activity: substitution of the isosteric 1H-benzimidazole, 1H-indazole, and 1H-benzotriazole with 1H-indole; variation of the N-heteroparaffino-side chain moiety; and placement of the N-heteroparaffinomethyl substituents in different positions relative to the 1-nitrogen, depending on the particular benzazole. The 3-substituted indoles are most toxic and very active, while the 1-substituted benzimidazoles are best tolerated. Seven benzazoles (at least one from each chemical class) produce unusually high motility. Some general observations are reported. Methylpiperidino derivatives produce the greatest responses studied.
Article
The new obtained N3-alkyl- or arylpiperazinoalkyl substituted derivatives of 5,5-diphenylhydantoin weakly affect the spontaneous motility and the hypermotility induced by amphetamine. They did not show the anticonvulsive activity. Compounds containing the methyl (or phenyl)-piperazine moiety connected by the three-carbon chain with the N3 atom of the hydantoin ring show the strongest activity in the potentiation of the central effect of DOPA.
Article
A congeneric series of 5-haloisatins was synthesised and tested for biological activity. Mannich bases and hydrazones of 5-chloro- and 5-iodoisatin were prepared and their structures were determined spectrophotometrically. Morphological deformations and inhibition of radiolabelled precursor incorporation into DNA were studied in HeLa cell culture; antimitotic activity was examined using a phyto test with Lepidium sativum L. I50 values were determined for the most interesting compounds. The results obtained can be interpreted in terms of the group contributions to the parent molecule. Introduction of iodine into the aromatic moiety of isatin (position 5) considerably increased inhibitory potency of the parent molecule. Furthermore, N-bis-(2-chloroethyl) and N-bis-(2-hydroxyethyl) groups, respectively, as amino components of some of the N-Mannich bases, markedly enhance the biological activities studied in this work.
Article
The hydrolysis kinetics of a series of N-Mannich bases of carboxamides, thioamides, and other NH-acidic compounds were studied to assess their suitability as prodrugs for various drugs. The pH-rate profiles for the compounds were determined at 37 degrees and were accounted for by assuming the spontaneous decomposition of both free and protonated Mannich bases. The reaction rate for the free base increased sharply with increasing steric effects of the amine component of the N-Mannich bases and also with increasing acidity of the amide component. N-Mannich bases may be potentially useful prodrugs for NH-acidic compounds such as various amides, and ureides and for amines.
Article
A series of 5-haloisatins were aminomethylated in position 1 and hydrazino groups were introduced in position 3. Synthesized N-Mannich bases and hydrazones were biologically tested against various kinds of bacteria and fungi. Results from these in vitro studies showed a considerable growth inhibition of some gram negative bacteria caused by chlorinated N-Mannich bases of isatin. Comparing the inhibition zones of the halogenated isatin N-Mannich bases with structural analogues of nonhalogenated ones as well as with isatin itself, an increase in antimicrobial activity was observed, thus, indicating the importance of both substituents, namely, halogen in position 5 and an amino moiety in position 1. The most biologically active compound was found to be diisopropylamino-N-Mannich base of 5-chloroisatin.
Mannich base derivatives of pharmacologically active compounds. Part IV. 3-Alkylaminomethyl derivatives of oxazolidine-2
  • M Eekstein
  • H Pa&o
EEkstein, M. and Pa&o. H.. Mannich base derivatives of pharmacologically active compounds. Part IV. 3-Alkylaminomethyl derivatives of oxazolidine-2,4-dione and
Mannich base derivatives of physiologically active compounds. Part V. N-alkylannnomethyl derivatives of imides of arylsuccinic acids
  • M Eckstein
  • A Zejc
  • A Klusek
Eckstein, M., Zejc, A. and Klusek, A., Mannich base derivatives of physiologically active compounds. Part V. N-alkylannnomethyl derivatives of imides of arylsuccinic acids. Diss. Pharm. Pharmacol., 19 (1967) 263-269.
Mannich base derivatives of pharmacologically active compounds Part III. 3-Alkylaminome~yl derivatives of 5,5-dialkylbarbituric acids
  • M Eckstein
  • A Zejc
  • J Sulko
Eckstein, M., Zejc, A. and Sulko, J., Mannich base derivatives of pharmacologically active compounds Part III. 3-Alkylaminome~yl derivatives of 5,5-dialkylbarbituric acids. Diss. Pharm. Pharmacol., 18 (1966) 131-137.
Mannich base derivatives of pharmacologically active compounds. Part XII. 2-Methyl and cis-2,5-dimethylpiperazine in the reaction of aminoalkylation of hydantoin and thiohydantoin derivatives
  • Lucka-Sobstel
Lucka-Sobstel, B. and Zejc, A., Mannich base derivatives of pharmacologically active compounds. Part XII. 2-Methyl and cis-2,5-dimethylpiperazine in the reaction of aminoalkylation of hydantoin and thiohydantoin derivatives. Diss. Pharm. Pharmacol., 22 ( 1970) 13-19.
Mannich base derivatives of pharmacologically active compounds. Part XIV. 2-Methyl and cis- or trans-2,5-dimethylpiperazine in the reaction of aminoalkylation of alkyland arylsuccinimides
  • Lucka-Sobstel
Lucka-Sobstel, B. and Zejc, A., Mannich base derivatives of pharmacologically active compounds. Part XIV. 2-Methyl and cis-or tram+2,Sdimethylpiperazine in the reaction of aminoalkylation of alkyl-and arylsuccinimides. Diss. Pharm. Pharmacol., 23 (1971) 135-140.