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At least 19 recordsLinked to original sources
PubMed2005

Synthesis and in-vitro cytotoxicity evaluation of gatifloxacin Mannich bases.

Mannich bases of gatifloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. The compounds were tested in-vitro against a panel of 58 human tumour cell lines derived from nine neoplastic diseases. Among them compound 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7[[N4-(3'-sulphadoximino)-1'-(5-bromoisatinyl) methyl]-3-methyl N1-piperazinyl]-3-quinoline carboxylic acid (6) emerged as a potent anticancer agent being more active than standard DNA topoisomerase II inhibitor, etoposide against 30 cancer cell lines.

Antineoplastic Agents↗
PubMed2000

Synthesis, antibacterial, antifungal and anti-HIV activities of norfloxacin mannich bases.

Mannich bases of norfloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. Investigation of in vitro antimicrobial activity of compounds was done by the agar dilution method against 28 pathogenic bacteria, eight pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. The in vivo antibacterial efficacy of selected derivatives was determined using a mouse infection model. All the synthesized compounds are more active than norfloxacin against the 13 bacteria tested. The compounds are also more active than the standard drug clotrimazole against Histoplasma capsulatum. Two compounds S-8 and S-9 have shown inhibition against HIV-1 (III B) with EC(50) values of 11.3 and 13.9 microgram/mL, respectively. In the mouse protection test, two compounds S-4 (ED(50): 1.25 mg/kg) and S-9 (ED(50): 1.62 mg/kg) are more active than norfloxacin (ED(50): 6mg/kg). Among the compounds tested, 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7[[N(4)-[5'-bromo-3'-(4'-amino-5'-trimethoxybenzylpyr imidin-2'-yl]-imino-1'-isatinyl]methyl]N(1)-piperazinyl]-3-q uinoline carboxylicacid (S-9) showed promising activity in all the three tests.

Animals↗
PubMed2003

Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity.

Thioredoxin reductase (TrxR) is the homodimeric flavoenzyme that catalyzes reduction of thioredoxin disulfide (Trx). For Plasmodium falciparum, a causative agent of tropical malaria, TrxR is an essential protein which has been validated as a drug target. The high-throughput screening of 350000 compounds has identified Mannich bases as a new class of TrxR mechanism-based inhibitors. During catalysis, TrxR conducts reducing equivalents from the NADPH-reduced flavin to Trx via the two redox-active cysteine pairs, Cys88-Cys93 and Cys535'-Cys540', referred to as N-terminal and C-terminal cysteine pairs. The structures of unsaturated Mannich bases suggested that they could act as bisalkylating agents leading to a macrocycle that involves both C-terminal cysteines of TrxR. To confirm this hypothesis, different Mannich bases possessing one or two electrophilic centers were synthesized and first studied in detail using glutathione as a model thiol. Michael addition of glutathione to the double bond of an unsaturated Mannich base (3a) occurs readily at physiological pH. Elimination of the amino group, promoted by base-catalyzed enolization of the ketone, is followed by addition of a second nucleophile. The intermediate formed in this reaction is an alpha,beta-unsaturated ketone that can react rapidly with a second thiol. When studying TrxR as a target of Mannich bases, we took advantage of the fact that the charge-transfer complex formed between the thiolate of Cys88 and the flavin in the reduced enzyme can be observed spectroscopically. The data show that it is the C-terminal Cys 535'-Cys540' pair rather than the N-terminal Cys88-Cys93 pair that is modified by the inhibitor. Although alkylated TrxR is unable to turn over its natural substrate Trx, it can reduce low M(r) electron acceptors such as methyl methanethiolsulfonate by using its unmodified N-terminal thiols. On the basis of results with chemically distinct Mannich bases, a detailed mechanism for the inactivation of TrxR is proposed.

Alkylating Agents↗
PubMed1987

Anticonvulsant activity of indanylspirosuccinimide Mannich bases.

A series of Mannich bases derived from spiro [indan-1,3'pyrrolidine-2',5'-dione] were evaluated for anticonvulsant activity. This activity varied as a function of the amine substituent and several compounds showed protective effects in both the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scMet) assays. In addition, fluorenyl- and cyclopentyl-derived spirosuccinimides, as well as extended chain analogues, were tested and proved to be inactive. A time versus effect study was conducted employing the MES assay and the hydroxyethylpiperazine-derived Mannich base of spiro [indan-1,3 pyrrolidine-2',5',dione]. This compound acted rapidly and its protective half-life was increased as larger doses were administered.

Amines↗
PubMed2005

Biocidal activity of some Mannich base cationic derivatives.

A novel series of cationic surfactants was prepared based on Mannich base (produced from the condensation of piperidine and/or morpholine as secondary amine and paraformaldehyde in the presence of 8-hydroxyquinoline). The chemical structures of the synthesized cationic surfactants were confirmed using elemental analyses, FTIR spectroscopy and 1H NMR. Surface activities of the prepared surfactants were measured including: surface tension (gamma), critical micelle concentration (CMC), effectiveness (pi(CMC)), efficiency (Pc20), maximum surface excess (Gamma(max)), minimum surface area (A(min)), interfacial tension (gamma(IT)), emulsification power and foaming power at 25 degrees C. The structural influences on their surface activities and adsorption free energy were discussed. The synthesized cationic surfactants were evaluated for their biocidal activity towards Gram +ve bacteria (Staph. Cocu., Bacillus), Gram -ve bacteria (Salmonella, E. coli), fungi (A. terrus., A. flav.) and yeast (Candida) at 1.0, 2.5 and 5.0mg/mL, respectively. The target compounds showed good inhibition towards Gram +ve bacteria, Gram -ve bacteria and yeast. Meanwhile, excellent fungicidal results were obtained against the various types of fungi under investigation.

Adsorption↗
PubMed1992

The chemotherapy of rodent malaria. XLVII. Studies on pyronaridine and other Mannich base antimalarials.

The activities of Mannich base antimalarials, including pyronaridine, have been explored against drug-sensitive (Plasmodium berghei N) and chloroquine-resistant (Plasmodium yoelii NS) rodent malaria parasites in vivo. Lines of these parasites have been developed with resistance to pyronaridine, amodiaquine, or WR 228,258. The responses and patterns of cross-resistance of these lines to Mannich bases and other blood schizontocides are inconsistent. It is concluded that some Mannich bases may prove still to be of value inthe treatment of chloroquine-resistant Plasmodium falciparum infection.

Aminoquinolines↗
PubMed2002

Cytotoxic activities of some mono and bis Mannich bases derived from acetophenone in brine shrimp bioassay.

Some mono Mannich bases (1-phenyl-3-amino-1-propanone salts) and bis Mannich bases (1-phenyl-3-amino-2-amino-methyl-1-propanone salts) derived from acetophenone and a few representative quaternary derivatives were synthesised and their cytotoxicity was tested using the brine shrimp bioassay. This assay may serve as an intermediate test before further in vivo animal experiments in large scale, since brine shrimp nauplii as whole organisms were used in this test. Mono Mannich bases were generally more cytotoxic than their corresponding bis Mannich bases. Mannich bases synthesised were cytotoxic in both brine shrimp bioassay in this study and cell culture tests using Jurkat and Renca cells in a previous study. However, the order of the cytotoxic potency of the compounds were reverse, which may result from faster deamination of bis derivatives than optimal level, and different species and test media used in the two test systems. Faster deamination of bis derivatives might have led to elimination of active metabolites before reaching its target. The cytotoxicity of the compounds might have been altered by amino acids and proteins present in cell culture medium but not in sea water used in brine shrimp bioassay affecting their transport through the cell membrane and metabolism in the cell by binding with the compounds. With higher cytotoxic activity compared with 5-fluorouracil (CAS 51-21-8) in brine shrimp bioassay, mono Mannich base 1 and its quaternary derivative 4 and quaternary bis derivative 8 seem to be candidate compounds for further drug design.

Acetophenones↗
PubMed1998

Cytotoxic activities of Mannich bases of chalcones and related compounds.

Various Mannich bases of chalcones and related compounds displayed significant cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of human tumor cell lines. The most promising lead molecule was 21 that had the highest activity toward L1210 and human tumor cells. In addition, 21 exerted preferential toxicity to human tumor lines compared to transformed human T-lymphocytes. Other compounds of interest were 38, with a huge differential in cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index when cytotoxicity to P388 cells and Molt 4/C8 T-lymphocytes were compared. In general, the Mannich bases were more cytotoxic than the corresponding chalcones toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the in vitro human tumor screen revealed that the mode of action of certain groups of compounds was similar. For some groups of compounds, cytotoxicity was correlated with the sigma, pi, or molar refractivity constants in the aryl ring attached to the olefinic group. In addition, the IC50 values in all three screens correlated with the redox potentials of a number of Mannich bases. X-ray crystallography and molecular modeling of representative compounds revealed various structural features which were considered to contribute to cytotoxicity. While a representative compound 15 was stable and unreactive toward glutathione (GSH) in buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the pi isozyme of glutathione S-transferase, suggesting that thiol alkylation may be one mechanism by which cytotoxicity was exerted in vitro. Representative compounds were shown to be nonmutagenic in an intrachromosomal recombination assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant and neurotoxic properties. Thus Mannich bases of chalcones represent a new group of cytotoxic agents of which 21 in particular serves as an useful prototypic molecule.

Animals↗
PubMed2000

Cytotoxic activities of mono and bis Mannich bases derived from acetophenone against Renca and Jurkat cells.

Mannich bases of acetophenones have been disclosed to have antitumour and cytotoxic activities. 1-Phenyl-3-dimethylaminopropan-1-one hydrochloride, 1, and related piperidino, 2, and morpholino, 3, derivatives, and compound 4, which is a quaternary form of 1, were synthesized as mono Mannich bases derived from acetophenone. They were converted to corresponding bis Mannich bases, 5-8, to see whether it increases the bioactivity. The biological activity of the compounds was examined by cytotoxicity against mouse renal carcinoma (Renca) and transformed human T-lymphocyte (Jurkat) cell lines. Conversion of mono Mannich bases to corresponding bis Mannich bases remarkably increased the cytotoxicity in most cases. Quaternization procedure also improved the bioactivity in mono derivatives against Jurkat cells. Bis mannich bases 5-7 were found to be more active than 5-fluorouracil (6-23 fold) and melphalan (1.25-5 fold) against Renca cells. Except 2 and 8, the compounds synthesised were found to be more active than 5-fluorouracil (1.2-33 fold) against Jurkat cells.

Acetophenones↗
PubMed2003

Cytotoxicity of some azines of acetophenone derived mono-Mannich bases against Jurkat cells.

Acetophenone derived mono-Mannich bases (Ig1-Ig4), 1-aryl-3-amino-1-propanone hydrochlorides, which are known to have cytotoxicity in Jurkat cells, were synthesized. Then, they were converted to corresponding azine derivatives (D1-D4), N, N'-bis(3-amino-1-aryl-propylidene)hydrazine dihydrochlorides, which are bifunctional agents. The aryl part was replaced by phenyl in Ig1, Ig2, Ig3, D1, D2, and D3, and by p-hydroxyphenyl in Ig4 and D4. The amine part was replaced by dimethylamine in Ig1, D1, Ig4 and D4, by piperidine in Ig2 and D2, and by morpholine in Ig3 and D3. The aim of this study was to investigate whether the modification in chemical structure, converting the mono-Mannich base to a corresponding azine derivative, improves the cytotoxicity. In addition, the effect of the representative compound, D3, N, N'-bis(3-morpholine-4-yl-1-phenylpropylidene)hydrazine dihydrochloride, on cellular glutathione level after 1 h exposure in phosphate buffer at 37 degrees C was also determined to provide information on a possible mechanism of cytotoxic action. Compounds D2-D4 are reported for the first time in this study. Except for Ig2 and D2, the cytotoxicity of mono-Mannich bases, Ig1, Ig3 and Ig4 and corresponding azine derivatives, D1, D3 and D4 were higher than the reference compound 5-FU. Azine derivatives D1 and D4 had almost equal cytotoxic potency with corresponding mono-Mannich bases Ig1 and Ig4, respectively. On the other hand, azine derivatives D2 and D3, had 1.28 and 1.90-times less cytotoxicity in Jurkat cells compared with the mono-Mannich bases, Ig2 and Ig3, respectively, from which they are derived. Azine derivative D3 dose-dependently decreased the total cellular glutathione level, suggesting that azine derivatives may exert cytotoxicity by thiol alkylation. Azine derivatives with equal or less cytotoxic potency compared to the mono-Mannich bases they are derived from seemed to be less suitable derivatives for the development of new cytotoxic compounds.

Acetophenones↗
PubMedDate not supplied

Neuropharmacological actions of some newly synthesized Mannich bases.

Benzamido (alkyl) methyl pyrrolidine Mannich bases were synthetized and subjected to certain neuropharmacological studies. All the bases reduced the pentobarbitone sleeping time and rota-rod grip of rats. The Mannich bases II, III and V raised the minimal electro-shock seizure threshold of rats. The TAB-induced pyrexia was not reduced by the bases I and III in rabbits. None of the bases showed any significant analgesic activity.

Amines↗
PubMed2005

Evaluation of antimicrobial activities of several mannich bases and their derivatives.

The aim of this study was to evaluate the antimicrobial activities of several Mannich bases and their derivatives against pathogenic bacteria and fungi. 3-Dimethylamino-1-phenyl-1-propanone hydrochloride (Ig1) as mono-Mannich base, bis(beta-aroylethyl)methylamine hydrochlorides (B1, B5) as bis-Mannich bases, 3-aroyl-4-aryl-1-methyl-4-piperidinol hydrochlorides (C1, C5) as piperidinol derivatives, which are structural isomers of bis-Mannich bases, N,N'-Bis(3-dimethylamino-1-phenylpropylidene)hydra zine dihydrochlorides (D1) as azine derivative of mono-Mannich base Ig1, and some representative quaternary derivatives (Ig4 and C6), which are quaternary derivatives of Ig1 and C1, respectively, have been synthesized. Aryl parts were phenyl in B1 and C1, and 2-thienyl in B5 and C5. Bis-Mannich bases and quaternary Mannich bases were found to be effective antifungal derivatives. Quaternary mono-Mannich base Ig4 has shown twice the amount of higher antifungal potency against the human pathogenic fungus Microsporum canis compared with the reference drug amphotericin-B and it had equal potency against many other fungi species pathogenic in humans and plants. Ig4 was effective against Staphylococcus aureus among the bacteria tested. Preparation of bis-Mannich bases and qua ternization procedure seemed suitable chemical modifications to prepare effective antifungal compounds. Especially quaternary derivatives Ig4, and to some extent C6, seem to be model compounds to develop new antimicrobial agents for further studies.

Anti-Bacterial Agents↗
PubMed2004

Antimycobacterial arylidenecyclohexanones and related Mannich bases.

Several series of 2-arylidenecyclohexanones and related Mannich bases as well as various 2,6-bis(arylidene)cyclohexanones were evaluated against Mycobacterium tuberculosis H37Rv. Using a concentration of 12.5 microg/ml, nearly half of the unsaturated ketones inhibited the growth of the microorganism by 21-66% while all of the Mannich bases achieved 99% or greater inhibition. The relative hydrophobicities and widths of the molecules may have been contributing factors as to whether bioactivity was present or absent. Two of the Mannich bases demonstrated noteworthy potencies towards Mycobacterium avium. The conclusion was drawn that Mannich bases of 2-arylidenecyclohexanones represent a novel class of antimycobacterials.

Animals↗
PubMed2001

Antifungal activity of some mono, bis and quaternary Mannich bases derived from acetophenone.

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.

Acetophenones↗
PubMedDate not supplied

Antituberculous activity of norfloxacin mannich bases with isatin derivatives.

Mannich bases of norfloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. The compounds were evaluated in vitro against Mycobacterium tuberculosis H37R(v) at 12.5 microg/ml in BACTEC 12B medium using the BACTEC radiometric system. Among the compounds tested, S-10 showed promising activity, with 100% inhibition at a concentration lower than 6.25 microg/ml.

Anti-Infective Agents↗
PubMed2002

Syntheses and stability studies of some Mannich bases of acetophenones and evaluation of their cytotoxicity against Jurkat cells.

Mannich bases, namely 1-aryl-3-dimethylamino-1-propanone hydrochlorides (Ia-f) as mono-Mannich bases (series I), bis(beta-aroylethyl)ethylamine hydrochlorides (IIa, IIb, IId, IIe) as bis-Mannich bases (series II), 3-aroyl-4-aryl-1-ethyl-4-piperidinol hydrochlorides (series III), which are structural isomers of bis derivatives and some representative quaternary salts (Ig, IIIf, IIIg), were synthesized to investigate the effect of chemical structure and ring substituents on cytotoxic activity in Jurkat cells. Stability studies of some representative compounds have also been realised. Compounds IIb, IId, IIe, and IIIe were reported for the first time. Id-g, IIa, IId, IIe, IIIf,g were 1.25-6.55 times more potent than 5-fluorouracil (CAS 51-21-8). However, the cytotoxic activity of the most potent compounds. Ig and IIIf, were one fifth of that of melphalan (CAS 148-82-3). The formation of compound IV during the stability studies of Ig, IIa, and IIIf suggested that they may be thiol alkylators. Bis-Mannich base IIa in nonsubstituted derivatives, piperidinol derivative IIIb in methyl substituted compounds, mono derivative Id in chloro substituted compounds were the most potent compounds when the cytotoxicity of the compound series which have the same substituents in benzene ring are compared. Replacement of the benzene with thiophene improved the cytotoxicity in both series I and II. Quaternization procedure also increased the cytotoxicity in both series I and III. Quaternary derivatives seem to be promising compounds for further studies to develop new anticancer drugs.

Acetophenones↗
PubMed2005

The effects of some Mannich bases on heat shock proteins HSC70 and GRP75, and thioredoxin and glutaredoxin levels in Jurkat cells.

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.

Glutaredoxins↗